FDA Drug Safety Communication: FDA strengthens kidney

warnings for diabetes medicines canagliflozin (Invokana,

Invokamet) and dapagliflozin (Farxiga, Xigduo XR)
[ 06-14-2016 ]

Safety Announcement

The U.S. Food and Drug Administration (FDA) has strengthened the existing warning
about the risk of acute kidney injury for the type 2 diabetes medicines canagliflozin
(Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). Based on recent reports,
we have revised the warnings in the drug labels to include information about acute
kidney injury and added recommendations to minimize this risk.

Patients should seek medical attention immediately if they experience signs and
symptoms of acute kidney injury. This is a serious condition in which the kidneys
suddenly stop working, causing dangerous levels of wastes to build up in the body. Signs
and symptoms of acute kidney injury may include decreased urine or swelling in the legs
or feet. Patients should not stop taking their medicine without first talking to their
health care professionals. Doing so can lead to uncontrolled blood sugar levels that can
be harmful.

Health care professionals should consider factors that may predispose patients to
acute kidney injury prior to starting them on canagliflozin or dapagliflozin. These
include decreased blood volume; chronic kidney insufficiency; congestive heart failure;
and taking other medications such as diuretics, blood pressure medicines called
angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers
(ARBs), and nonsteroidal anti-inflammatory drugs (NSAIDs). Assess kidney function
prior to starting canagliflozin or dapagliflozin and monitor periodically thereafter. If
acute kidney injury occurs, promptly discontinue the drug and treat the kidney
impairment.

Canagliflozin and dapagliflozin are prescription medicines used with diet and exercise to
help lower blood sugar in adults with type 2 diabetes. They belong to a class of drugs
called sodium-glucose cotransporter-2 (SGLT2) inhibitors. Canagliflozin and
dapagliflozin lower blood sugar by causing the kidneys to remove sugar from the body
through the urine. Untreated, type 2 diabetes can lead to serious problems, including
blindness, nerve and kidney damage, and heart disease.
From March 2013, when canagliflozin was approved, to October 2015, FDA received
reports of 101 confirmable cases* of acute kidney injury, some requiring hospitalization
and dialysis, with canagliflozin or dapagliflozin use (see Data Summary). This number
includes only reports submitted to FDA, so there are likely additional cases about which
we are unaware. In approximately half of the cases, the events of acute kidney injury
occurred within 1 month of starting the drug, and most patients improved after stopping
it. Some cases occurred in patients who were younger than 65 years. Some patients were
dehydrated, had low blood pressure, or were taking other medicines that can affect the
kidneys.

We urge health care professionals and patients to report side effects involving
canagliflozin, dapagliflozin, or other medicines to the FDA MedWatch program, using
the information in the “Contact FDA” box at the bottom of the page.

*The cases were reported to the FDA Adverse Event Reporting System (FAERS) (/fda-
adverse-event-reporting-system-faers).

Facts about canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR)

Canagliflozin and dapagliflozin are prescription medicines that are used along with
diet and exercise to lower blood sugar in adults with type 2 diabetes. They belong
to a class of drugs called sodium-glucose cotransporter-2 (SGLT2) inhibitors.
Canagliflozin and dapagliflozin are available as single-ingredient products under
the brand names Invokana and Farxiga. They are also available in combination
with the diabetes medicine metformin under the brand names Invokamet and
Xigduo XR.
Canagliflozin and dapagliflozin lower blood sugar by causing the kidneys to
remove sugar from the body through the urine.
In addition to acute kidney injury, some other possible side effects of canagliflozin
or dapagliflozin include low blood pressure, a condition of too much acid in the
blood called ketoacidosis, serious urinary tract infections, and yeast infections.
Combining canagliflozin or dapagliflozin with other prescription diabetes
medicines can increase the likelihood of low blood sugar.
During the 12 month period from October 2014 through September 2015,
approximately 1.5 million unique patients received a dispensed prescription for
canagliflozin or dapagliflozin-containing product through outpatient U.S. retail
pharmacies.1

Additional Information for Patients

 Cases of acute kidney injury, some requiring hospitalization and dialysis, have
been reported in patients receiving canagliflozin (Invokana, Invokamet) or
dapagliflozin (Farxiga, Xigduo XR).

About half of the cases occurred within 1 month of starting canagliflozin or

dapagliflozin, and most patients improved after stopping the drug.

Before starting canagliflozin or dapagliflozin, tell your health care professional if

you are taking other medicines that may also affect the kidneys such as water pills,
blood pressure medicines, or nonsteroidal anti-inflammatory drugs (NSAIDs) such
as aspirin, ibuprofen, or naproxen.
Seek medical attention immediately if you experience signs and symptoms while
taking these medicines such as:
Decreased urine
Swelling in your legs or feet
Talk with your health care professional immediately if you are:

Eating or drinking less due to illness or fasting

Losing fluids due to vomiting, diarrhea, or excessive heat exposure
Your health care professional may determine it is appropriate to temporarily stop
taking canagliflozin or dapagliflozin in these situations.
Do not stop or change your diabetes medicines without first talking to your health
care professional. Doing so can lead to uncontrolled blood sugar levels that can be
harmful. Over time, uncontrolled blood sugar levels can cause serious problems,
including blindness, nerve and kidney damage, and heart disease.
Read the patient Medication Guide (/drugs/drug-safety-and-
availability/medication-guides) you receive with your canagliflozin or dapagliflozin
prescriptions. It explains the benefits and risks associated with the medicine.
Talk to your health care professional if you have questions or concerns about
canagliflozin, dapagliflozin, or any other diabetes medicines.

Report side effects from canagliflozin, dapagliflozin, or other medicines to the FDA
MedWatch program, using the information in the "Contact FDA" box at the
bottom of this page.

Additional Information for Health Care Professionals

Postmarketing cases of acute kidney injury, some requiring hospitalization and

dialysis, have been reported in patients receiving canagliflozin (Invokana,
Invokamet) or dapagliflozin (Farxiga, Xigduo XR).
In approximately half of the cases, acute kidney injury occurred within 1 month of
starting the drug, and most patients improved after discontinuing the drug.
 Before initiating canagliflozin or dapagliflozin, consider factors that may
predispose patients to acute kidney injury. These include hypovolemia, chronic
renal insufficiency, congestive heart failure, and concomitant medications such as
diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor
blockers (ARBs), and nonsteroidal anti-inflammatory drugs (NSAIDs).
Evaluate renal function prior to initiating canagliflozin or dapagliflozin and
monitor periodically thereafter.

Consider temporarily discontinuing canagliflozin or dapagliflozin in any setting of

reduced oral intake such as acute illness or fasting, or with 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 canagliflozin or dapagliflozin promptly and institute
treatment.

Encourage patients to read the Medication Guide (/drugs/drug-safety-and-

availability/medication-guides) they receive with their canagliflozin or
dapagliflozin prescriptions.
Report adverse events involving canagliflozin, dapagliflozin, or other drugs to the
FDA MedWatch program, using the information in the "Contact FDA" box at the
bottom of this page.

Data Summary

A search of the FDA Adverse Event Reporting System (FAERS) database (/fda-adverse-
event-reporting-system-faers) from March 29, 2013, to October 19, 2015, identified 101
cases of acute kidney injury with sufficient detail to confirm the diagnosis and
demonstrate a temporal relationship with canagliflozin (73 patients) and dapaglifozin
(28 patients). Hospitalization for evaluation and management of acute kidney injury was
necessary in 96 of the 101 cases, and 22 cases involved admission to an intensive care
unit. Four deaths occurred during hospitalization, 2 of which were cardiac-related.
Fifteen patients received dialysis, and of these, 3 patients had a history of chronic kidney
disease or previous acute kidney injury, and 6 reported concomitant use of both an
angiotensin-converting enzyme (ACE) inhibitor and a diuretic. In 58 cases, the time to
onset of acute kidney injury occurred within one month or less of initiating the drug.

The median age of the patients was 57 years (range 28-79 years). Among the 84 cases
that reported an age, more than half were in patients who were 60 years or younger. Of
the 101 cases, 51 reported concomitant ACE inhibitor use, 26 reported concomitant
diuretic use, and 6 reported concomitant nonsteroidal anti-inflammatory drug (NSAID)
use. A prior history of chronic kidney disease was reported in 10 of the 101 cases. In
some cases, dehydration or hypotension was reported. Forty-five of the 101 cases
reported a change in renal function (serum creatinine (SCr) or estimated glomerular
 filtration rate (eGFR)) at the time of diagnosis. The median elevation of SCr from
baseline in 32 patients was 1.6 mg/dL. In 13 cases that only reported eGFR at baseline
and during the acute kidney injury event, the median decrease in eGFR was 46
mL/min/1.73 m2.

In the 78 cases reporting drug discontinuation, 56 cases reported improvement,

demonstrating reversibility of this adverse event in a majority of cases. Eleven patients
did not recover, which included the 4 deaths noted previously. Three patients recovered
with sequelae upon discontinuation, suggesting that kidney injury may not be fully
reversible in some situations.

References

1. IMS Health, Total Patient Tracker (TPT), DATA 2015-2308 SGLT2 Inhibitor
DSC.xlsx.

en Español (/drugs/drug-safety-and-availability/la-fda-refuerza-las-advertencias-
relacionadas-con-el-rinon-para-los-medicamentos-para-la-diabetes)

Drug Safety Communication (/media/98683/download) (PDF - 59KB)

Related Information
Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors (/drugs/postmarket-drug-safety-
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The FDA's Drug Review Process: Ensuring Drugs Are Safe and Effective
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Think It Through: Managing the Benefits and Risks of Medicines (/drugs/information-

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