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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.
QTERN (NDA-209091)
(DAPAGLIFLOZIN; SAXAGLIPTIN HYDROCHLORIDE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
09/12/2023 (SUPPL-8)
5 Warnings and Precautions
5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other KetoacidosisNewly added subsection:
In patients with type 1 diabetes mellitus, dapagliflozin, a component of QTERN, 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 cotransporter 2 (SGLT2) inhibitors compared to patients who received placebo. QTERN 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 dapagliflozin.
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 QTERN [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 QTERN, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting QTERN.
Withhold QTERN, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume QTERN when the patient is clinically stable and has resumed oral intake [see DOSAGE AND ADMINISTRATION (2.5)].
Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue QTERN 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 or 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 GuideExtensive changes; please refer to label
Newly added information:
Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
Inform patients that QTERN 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 QTERN and seek medical attention immediately [see WARNINGS AND PRECAUTIONS (5.1)].
. . .
Educate patients on the signs and symptoms of hypoglycemia
10/13/2022 (SUPPL-7)
7 Drug Interactions
Changes to Table 2 to add interactions with insulin, insulin secretagogues (e.g. sulfonylurea), and lithium
03/04/2022 (SUPPL-6)
5 Warnings and Precautions
5.3 Ketoacidosis
Additions and/or revisions underlined:
Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have been identified in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose cotransporter-2 (SGLT2) inhibitors, including dapagliflozin [see ADVERSE REACTIONS (6.1)]. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. Fatal cases of ketoacidosis have been reported in patients taking dapagliflozin. QTERN is not indicated for the treatment of patients with type 1 diabetes mellitus [see INDICATIONS AND USAGE (1)].
5.4 Volume Depletion
Additions and/or revisions underlined:
Dapagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. 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 dapagliflozin. Patients with impaired renal function (eGFR <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 QTERN in patients with one or more of these characteristics, assess volume status and renal function. QTERN is contraindicated in patients with an eGFR <45 mL/min/1.73 m2. Monitor for signs and symptoms of hypotension, and renal function after initiating therapy.
5.5 Urosepsis and Pyelonephritis
Additions and/or revisions underlined:
Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including dapagliflozin. Treatment with SGLT2 inhibitors 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 (6.2)].
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
Dapagliflozin
Initiation of SGLT2 inhibitors, including dapagliflozin causes a small increase in serum creatinine and decrease in eGFR. These changes in serum creatinine and eGFR generally occur within two weeks of starting therapy and then stabilize regardless of baseline kidney function. Changes that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury. In two studies that included patients with type 2 diabetes mellitus with moderate renal impairment, the acute effect on eGFR reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with dapagliflozin.
8 Use in Specific Populations
8.4 Renal Impairment
Additions and/or revisions underlined: Dapagliflozin
Dapagliflozin was evaluated in two glycemic control studies that included patients with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m2, and an eGFR of 30 to less than 60 mL/min/1.73 m2). Patients with diabetes and renal impairment using dapagliflozin for glycemic control may be more likely to experience hypotension and may be at higher risk for acute kidney injury secondary to volume depletion. In the study of patients with an eGFR 30 to less than 60 mL/min/1.73 m2, 13 patients receiving dapagliflozin experienced bone fractures compared to none receiving placebo.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
Volume Depletion
Additions and/or revisions underlined:
Dapagliflozin
Inform patients that symptomatic hypotension may occur with QTERN and advise them to contact their healthcare provider if they experience such symptoms. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake [see WARNINGS AND PRECAUTIONS (5.4)].
Medication Guide
Extensive changes; please refer to labeling
01/24/2020 (SUPPL-5)
5 Warnings and Precautions
5.4 Ketoacidosis(Additions and/or revisions underlined)
Before initiating QTERN, 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 elective surgery, consider temporarily discontinuing QTERN for at least 3 days prior to surgery.
Consider monitoring for ketoacidosis and temporarily discontinuing QTERN 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 QTERN.
Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue QTERN and seek medical attention immediately if signs and symptoms occur.
(Additions and/or revisions underlined)
Dapagliflozin causes intravascular volume contraction, and can cause acute kidney injury. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving dapagliflozin.
Increases in serum creatinine and decreases in estimated GFR may also be observed with initiation of QTERN. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Before initiating QTERN, 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, and NSAIDs). Consider temporarily discontinuing QTERN in the 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 QTERN promptly and institute treatment.
Renal function should be evaluated prior to initiation of QTERN and monitored periodically thereafter. QTERN is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2.
6 Adverse Reactions
6.1 Clinical Trials Experience(Extensive changes; please refer to label)
8 Use in Specific Populations
8.4 Geriatric Use(Additions and/or revisions underlined)
Because elderly patients are more likely to have decreased renal function, care should be taken when using QTERN in the elderly based on renal function.
Dapagliflozin
A total of 1424 (24%) of the 5936 dapagliflozin-treated patients were 65 years and older and 207 (3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical studies assessing the efficacy of dapagliflozin in improving glycemic control. After controlling for level of renal function (eGFR), in clinical studies with dapagliflozin, efficacy was similar for patients under age 65 years and those 65 years and older. In patients 65 years and older, a higher proportion of patients treated with dapagliflozin had adverse reactions of hypotension.
(Additions and/or revisions underlined)
QTERN is contraindicated in patients with moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), ESRD, or on dialysis.
Dapagliflozin
Dapagliflozin was evaluated in two glycemic control studies that included patients with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m2, and an eGFR of 30 to less than 60 mL/min/1.73 m2). The safety profile of dapagliflozin in the study of patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 was similar to the general population of patients with type 2 diabetes.
Although patients in the dapagliflozin arm had reduction in eGFR compared to the placebo arm, eGFR generally returned towards baseline after treatment discontinuation. Patients with renal impairment using dapagliflozin for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury. In the study of patients with an eGFR 30 to less than 60 mL/min/1.73 m2, 13 patients receiving dapagliflozin experienced bone fractures compared to none receiving placebo.
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 dapagliflozin, 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 QTERN and seek medical attention immediately.
Administration
- Instruct patients that QTERN must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.
Missing Dose
- If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of QTERN at the same time.
07/01/2019 (SUPPL-4)
6 Adverse Reactions
6.2 Postmarketing Experience(additions underlined)
…
- Rhabdomyolysis
05/02/2019 (SUPPL-2)
5 Warnings and Precautions
5.5 Acute Kidney Injury and Impairment in Renal Function(addition underlined)
… Renal function should be evaluated prior to initiation of QTERN and monitored periodically thereafter. QTERN is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2
6 Adverse Reactions
6.1 Clinical Trials Experience(additions and revisions, please refer to label for more information)
8 Use in Specific Populations
8.1 Pregnancy(additions underlined)
…
Data
Animal Data
Dapagliflozin
…
In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation Day 6 through lactation Day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in 21 day-old pup offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415-times and 137-times, respectively, the human values at the 10 mg clinical dose, based on AUC). Dose-related reductions in pup body weights were observed at greater than or equal to 29-times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints were noted at 1 mg/kg/day, (19-times the 10 mg clinical dose, based on AUC). These outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development.
embryo-fetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441-times the 10 mg clinical dose, based on AUC). Dose related effects on the rat fetus (structural abnormalities and reduced body weight) occurred only at higher dosages, equal to or greater than 150 mg/kg (more than 2344-times the 10 mg clinical dose, based on AUC), which were associated with maternal toxicity. No developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on AUC).
…
(additions underlined)
Risk Summary
There is no information regarding the presence of QTERN or its components (dapagliflozin and saxagliptin) in human milk, the effects on the breastfed infant, or the effects on milk production.
Dapagliflozin and saxagliptin are present in the milk of lactating rats [see Data]. However, due to species specific differences in lactation physiology, the clinical relevance of these data is not clear. 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, advise women that use of QTERN is not recommended while breastfeeding.
…
(additions underlined)
QTERN is contraindicated in patients with moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), ESRD, or on dialysis.
Dapagliflozin
In clinical studies dapagliflozin was associated with increases in serum creatinine and decreases in eGFR.
Dapagliflozin was evaluated in a study that included patients with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m2). The safety profile of dapagliflozin in the study of patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 was similar to the general population of patients with type 2 diabetes. Although patients in the dapagliflozin arm had reduction in eGFR compared to the placebo arm, eGFR generally returned towards baseline after treatment discontinuation.