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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
STEGLATRO (NDA-209803)
(ERTUGLIFLOZIN)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/20/2024 (SUPPL-8)
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
…
Lower Limb Amputation
In a long-term cardiovascular outcomes study [see Clinical Studies (14.2)], in patients with type 2 diabetes mellitus and established cardiovascular disease, the occurrence of non-traumatic lower limb amputations was reported with event rates of 4.7, 5.7, and 6.0 events per 1,000 patient-years in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg treatment arms, respectively.
Across seven STEGLATRO clinical trials, non-traumatic lower limb amputations were reported in 1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the STEGLATRO 5 mg group, and 8 (0.5%) patients in the STEGLATRO 15 mg group.
…
6.2 Postmarketing Experience
Additions and/or revisions underlined:
…
Skin and Subcutaneous Tissue Disorders: angioedema, rash
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or revisions underlined:
…
Lower Limb Amputation
Inform patients of the potential for an increased risk of amputations. 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 (5.2)].
…
09/12/2023 (SUPPL-7)
5 Warnings and Precautions
5.1 Diabetic KetoacidosisSubsection title revised
Additions and revisions underlined:
in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
In patients with type 1 diabetes mellitus, STEGLATRO 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 transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may
be greater with higher doses. STEGLATRO 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.
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 4 days after discontinuing STEGLATRO [see Clinical Pharmacology (12.2)]; however, there have been
postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks
after discontinuation of SGLT2 inhibitors.
Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation.
Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs
and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue
STEGLATRO, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of
ketoacidosis before restarting STEGLATRO.
Withhold STEGLATRO, if possible, in temporary clinical situations that could predispose patients to
ketoacidosis. Resume STEGLATRO when the patient is clinically stable and has resumed oral intake [see
Dosage and Administration (2.3)].
Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue
STEGLATRO and seek medical attention immediately if signs and symptoms occur.
6 Adverse Reactions
Additions and revisions underlined:
The following important adverse reactions are described elsewhere in the labeling:
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis [see Warnings
and Precautions (5.1)]
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication GuideExtensive changes; please refer to label
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
Inform patients that STEGLATRO 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 STEGLATRO and seek medical attention immediately [see Warnings and
Precautions (5.1)].
10/13/2022 (SUPPL-6)
7 Drug Interactions
Newly added information to Table 7: Clinically Significant Drug Interactions with STEGLATRO
Lithium
Clinical Impact:
Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.
Intervention:
Monitor serum lithium concentration more frequently during STEGLATRO initiation and dosage changes.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication GuideNewly added information:
STEGLATRO may affect the way other medicines work, and other medicines may affect how STEGLATRO works.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
09/17/2021 (SUPPL-4)
4 Contraindications
(Additions and/or revisions underlined)
Hypersensitivity to ertugliflozin or any excipient in STEGLATRO, reactions such as angioedema have occurred [see Adverse Reactions (6.2)].
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 STEGLATRO [see Adverse Reactions (6.1)]. Fatal cases of ketoacidosis have been reported in patients taking SGLT2 inhibitors. 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. The risk of ketoacidosis may be greater with higher doses. STEGLATRO is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].
(Newly added section)
In a long-term cardiovascular outcomes study [see Clinical Studies 14.2], in patients with type 2 diabetes and established cardiovascular disease, the occurrence of non-traumatic lower limb amputations was reported with event rates of 4.7, 5.7, and 6.0 events per 1000 patient-years in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg treatment arms, respectively.
Amputation of the toe and foot were most frequent (81 out of 109 patients with lower limb amputations). Some patients had multiple amputations, some involving both lower limbs.
Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. Patients with amputations were more likely to be male, have higher A1C (%) at baseline, have a history of peripheral arterial disease, amputation or peripheral revascularization procedure, diabetic foot, and to have been taking diuretics or insulin.
Across seven STEGLATRO clinical trials , non-traumatic lower limb amputations were reported in 1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the STEGLATRO 5 mg group, and 8 (0.5%) patients in the STEGLATRO 15 mg group.
Before initiating STEGLATRO, consider factors in the patient history that may predispose them to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving STEGLATRO for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue STEGLATRO if these complications occur.
(Newly added section)
STEGLATRO can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including STEGLATRO. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2) [see Use in Specific Populations (8.6)], elderly patients, patients with low systolic blood pressure, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating STEGLATRO 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 STEGLATRO. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.
6 Adverse Reactions
(Additions and/or revisions underlined)
The following important adverse reactions are described elsewhere in the labeling:
Lower Limb Amputation [see Warnings and Precautions (5.2)]
Volume Depletion [see Warnings and Precautions (5.3)]
(Newly added information)
Ketoacidosis
In a long-term cardiovascular outcomes study VERTIS CV (eValuation of ERTugliflozin effIcacy and Safety, CardioVascular, [see Clinical Studies (14.2)]), a study in patients with type 2 diabetes and established cardiovascular disease, ketoacidosis was identified in 19 (0.3%) STEGLATRO-treated patients and in 2 (0.1%) placebo treated patients. Across seven other STEGLATRO clinical trials, ketoacidosis was identified in 3 (0.1%) STEGLATRO-treated patients and 0.0% of comparator-treated patients.
Urinary Tract Infections
In VERTIS CV, urinary tract infections (e.g., urinary tract infection, cystitis, dysuria) occurred in 10.2%, 12.2% and 12.0% of patients treated with placebo, STEGLATRO 5 mg and STEGLATRO 15 mg, respectively. The incidences of serious urinary tract infections were 0.8%, 0.9% and 0.4% with placebo, STEGLATRO 5 mg and STEGLATRO 15 mg, respectively.
Laboratory Tests
Changes in Serum Creatinine and eGFR
Initiation of STEGLATRO 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, an initial increase in serum creatinine and a decrease in eGFR within weeks of starting therapy was observed (at Week 6 eGFR changes of -2.7, -3.8 and -0.4 mL/min/1.73 m2 in the STEGLATRO 5 mg, STEGLATRO 15 mg and placebo arms, respectively). The initial decline was followed by a recovery toward baseline to Week 52 (eGFR change from baseline of - 0.4, - 1.1 and - 0.2 ml/min/1.73 m2 in STEGLATRO 5 mg, STEGLATRO 15 mg, and placebo arms, respectively). Acute hemodynamic changes may play a role in the early renal function changes observed with STEGLATRO since they are reversed after treatment discontinuation.
(Additions and/or revisions underlined)
Additional adverse reactions have been identified during postapproval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Necrotizing fasciitis of the perineum (Fournier’s Gangrene)
Angioedema
8 Use in Specific Populations
8.4 Geriatric Use(Newly added information)
In VERTIS CV, a total of 2780 (50.5%) patients treated with STEGLATRO were 65 years and older, and 595 (10.8%) patients treated with STEGLATRO were 75 years and older. Safety and efficacy were generally similar for patients age 65 years and older compared to patients younger than 65.
(Newly added information)
A 26-week placebo-controlled study of 313 patients with Stage 3 Chronic Kidney Disease (eGFR > or equal to 30 to less than 60 mL/min/1.73 m2) treated with STEGLATRO did not demonstrate improvement in glycemic control.
In the VERTIS CV study, there were 1370 patients (25%) with an eGFR > or equal to 90 mL/min/1.73 m2, 2929 patients (53%) with an eGFR of > or equal to 60 to less than 90 mL/min/1.73 m2, 879 patients (16%) with an eGFR of > or equal to 45 to less than 60 mL/min/1.73 m2, and 299 patients (5%) with eGFR of 30 to <45 mL/min/1.73 m2 treated with STEGLATRO. Similar effects on glycemic control at Week 18 were observed in patients treated with STEGLATRO in each eGFR subgroup and also in the overall patient population.
STEGLATRO is contraindicated in patients on dialysis [see Contraindications (4)].
No dosage adjustment is needed in patients with eGFR > or equal to 45 mL/min/1.73 m2.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide(Additions and/or revisions underlined)
STEGLATRO may cause serious side effects, including:
• Amputations. STEGLATRO may increase your risk of lower limb amputations.
There have been reports of sudden worsening of kidney function in people who are taking STEGLATRO.
What is STEGLATRO?
• STEGLATRO is a prescription medicine used in adults with type 2 diabetes to improve blood sugar
(glucose) control along with diet and exercise.
• STEGLATRO is not for people with type 1 diabetes. It may increase the risk of diabetic ketoacidosis
in these people.
01/24/2020 (SUPPL-2)
5 Warnings and Precautions
5.2 Ketoacidosis(Additions and/or revisions underlined)
Before initiating STEGLATRO, 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 STEGLATRO for at least 4 days prior to surgery.
Consider monitoring for ketoacidosis and temporarily discontinuing STEGLATRO 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 STEGLATRO.
Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue STEGLATRO 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 STEGLATRO, 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 STEGLATRO and seek medical attention immediately.
(Extensive changes to table; please refer to label)
10/26/2018 (SUPPL-1)
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 STEGLATRO 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 STEGLATRO, 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)
Newly added subsection:
6.2 Postmarketing Experience
Additional adverse reactions have been identified during postapproval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cases of necrotizing fasciitis of the perineum (Fournier’s gangrene) have been seen with SGLT2 inhibitors.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEWhat are the possible side effects of STEGLATRO? STEGLATRO may cause serious side effects, including:
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 medicines that lower blood sugar in the same way as STEGLATRO. 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.
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 SGLT2 inhibitors. 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.