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.

QTERNMET XR (NDA-210874)

(DAPAGLIFLOZIN; METFORMIN HYDROCHLORIDE; SAXAGLIPTIN HYDROCHLORIDE)

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

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01/24/2020 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Ketoacidosis

(Additions and/or revisions underlined)

Before initiating QTERNMET XR, consider factors in the patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse.

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

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

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

5.6 Acute Kidney Injury

(Additions and/or revisions underlined)

Dapagliflozin causes intravascular volume contraction 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 dapagliflozin. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Before initiating QTERNMET XR, 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 QTERNMET XR 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 QTERNMET XR promptly and institute treatment.

Renal function should be evaluated prior to initiation of QTERNMET XR and monitored periodically thereafter. QTERNMET XR 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/or revisions underlined)

Ketoacidosis

Dapagliflozin

In the cardiovascular outcome study with dapagliflozin in patients with type 2 diabetes mellitus, events of diabetic ketoacidosis were reported in 27 out of 8574 patients in the dapagliflozin-treated group and in 12 out of 8569 patients in the placebo group. The events were evenly distributed over the study period.

Laboratory Findings

Increases in Serum Creatinine and Decreases in eGFR

Dapagliflozin

Initiation of dapagliflozin causes an increase in serum creatinine and decrease in eGFR. In patients with normal or mildly impaired renal function at baseline, the serum creatinine and eGFR returned to baseline at Week 24. Sustained decreases in eGFR were seen in patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2).

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

Because metformin is eliminated by the kidney and because elderly patients are more likely to have decreased renal function, more frequent assessment of renal function is recommended in elderly patients.

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.

Metformin hydrochloride

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients.

8.6 Renal Impairment

(Additions and/or revisions underlined)

QTERNMET XR 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 a 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 QTERNMET XR and seek medical attention immediately.

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 QTERNMET XR at the same time.

07/01/2019 (SUPPL-1)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

…

Rhabdomyolysis