Included as part of the PRECAUTIONS section.
There have been post-marketing cases of
metformin-associated lactic acidosis, including fatal cases. These cases had a
subtle onset and were accompanied by nonspecific symptoms such as malaise,
myalgias, abdominal pain, respiratory distress or increased somnolence;
however, hypothermia, hypotension and resistant bradyarrhythmias have occurred
with severe acidosis.
Metformin-associated lactic acidosis was characterized by
elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis
(without evidence of ketonuria or ketonemia), and an increased lactate:
pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin
decreases liver uptake of lactate increasing lactate blood levels which may
increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected,
general supportive measures should be instituted promptly in a hospital
setting, along with immediate discontinuation of QTERNMET XR.
In QTERNMET XR-treated patients with a diagnosis or
strong suspicion of lactic acidosis, prompt hemodialysis is recommended to
correct the acidosis and remove accumulated metformin (metformin hydrochloride
is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic
conditions). Hemodialysis has often resulted in reversal of symptoms and
Educate patients and their families about the symptoms of
lactic acidosis and if these symptoms occur instruct them to discontinue
QTERNMET XR and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for
metformin-associated lactic acidosis, recommendations to reduce the risk of and
manage metformin-associated lactic acidosis are provided below:
The postmarketing metformin-associated lactic acidosis
cases primarily occurred in patients with significant renal impairment. The
risk of metformin accumulation and metformin-associated lactic acidosis
increases with the severity of renal impairment because metformin is
substantially excreted by the kidney. Clinical recommendations [see DOSAGE
AND ADMINISTRATION and CLINICAL PHARMACOLOGY] based upon the
patient's renal function include:
- Before initiating QTERNMET XR, obtain an estimated
glomerular filtration rate (eGFR).
- Obtain an eGFR at least annually in all patients taking
QTERNMET XR. In patients at increased risk for the development of renal
impairment (e.g., the elderly), renal function should be assessed more
- QTERNMET XR is contraindicated in patients with an eGFR
less than 45 mL/minute/1.73 m² [see CONTRAINDICATIONS, Use In
The concomitant use of QTERNMET XR with specific drugs
may increase the risk of metformin-associated lactic acidosis: those that
impair renal function, result in significant hemodynamic change, interfere with
acid-base balance, or increase metformin accumulation (e.g., cationic drugs) [see
DRUG INTERACTIONS]. Therefore, consider more frequent monitoring of
Age 65 Or Greater
The risk of metformin-associated lactic acidosis
increases with the patient's age because elderly patients have a greater
likelihood of having hepatic, renal or cardiac impairment than younger
patients. Assess renal function more frequently in elderly patients [see Use
In Specific Populations].
Radiological Studies With Contrast
Administration of intravascular iodinated contrast agents
in metformin-treated patients has led to an acute decrease in renal function
and the occurrence of lactic acidosis. Stop QTERNMET XR at the time of, or
prior to, an iodinated contrast imaging procedure in patients with a history of
hepatic impairment, alcoholism, or heart failure; or in patients who will be
administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after
the imaging procedure, and restart QTERNMET XR if renal function is stable.
Surgery And Other Procedures
Withholding of food and fluids during surgical or other
procedures may increase the risk for volume depletion, hypotension and renal
impairment. QTERNMET XR should be temporarily discontinued while patients have
restricted food and fluid intake.
Several of the postmarketing cases of
metformin-associated lactic acidosis occurred in the setting of acute
congestive heart failure (particularly when accompanied by hypoperfusion and
hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction,
sepsis and other conditions associated with hypoxemia have been associated with
lactic acidosis and may also cause prerenal azotemia. When such events occur,
discontinue QTERNMET XR.
Excessive Alcohol Intake
Alcohol potentiates the effect of metformin on lactate
metabolism and this may increase the risk of metformin-associated lactic
acidosis. Warn patients against excessive alcohol intake while receiving
Patients with hepatic impairment have developed with
cases of metforminassociated lactic acidosis. This may be due to impaired
lactate clearance resulting in higher lactate blood levels. Therefore, avoid
use of QTERNMET XR in patients with clinical or laboratory evidence of hepatic
There have been postmarketing reports of acute
pancreatitis in patients taking saxagliptin. In a cardiovascular outcomes trial
enrolling participants with established atherosclerotic cardiovascular disease
(ASCVD) or multiple risk factors for ASCVD (SAVOR trial), cases of definite
acute pancreatitis were confirmed in 17 of 8240 (0.2%) patients receiving
saxagliptin compared to 9 of 8173 (0.1%) receiving placebo. Pre-existing risk
factors for pancreatitis were identified in 88% (15/17) of those patients receiving
saxagliptin and in 100% (9/9) of those patients receiving placebo.
After initiation of QTERNMET XR, observe patients for
signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly
discontinue QTERNMET XR and initiate appropriate management. It is unknown
whether patients with a history of pancreatitis are at increased risk for the
development of pancreatitis while using QTERNMET XR.
In a cardiovascular outcomes trial enrolling participants
with established ASCVD or multiple risk factors for ASCVD (SAVOR trial), more
patients randomized to saxagliptin (289/8280, 3.5%) were hospitalized for heart
failure compared to patients randomized to placebo (228/8212, 2.8%). In a
time-to-first-event analysis, the risk of hospitalization for heart failure was
higher in the saxagliptin group (estimated Hazard Ratio: 1.27; 95% CI: 1.07,
1.51). Subjects with a prior history of heart failure and subjects with renal
impairment had a higher risk for hospitalization for heart failure,
irrespective of treatment assignment.
Consider the risks and benefits of QTERNMET XR prior to
initiating treatment in patients at a higher risk of heart failure. Observe
patients for signs and symptoms of heart failure during therapy. Advise
patients of the characteristic symptoms of heart failure and to immediately
report such symptoms. If heart failure develops, evaluate and manage according
to current standards of care and consider discontinuation of QTERNMET XR.
Dapagliflozin causes intravascular volume contraction.
Symptomatic hypotension can occur after initiating QTERNMET XR [see ADVERSE
REACTIONS] particularly in patients with impaired renal function (eGFR
<60 mL/min/1.73 m²), elderly patients or patients on loop diuretics. Before
initiating QTERNMET XR, volume status should be assessed and corrected.
QTERNMET XR is contraindicated in patients with an eGFR <45 mL/min/1.73 m².
Monitor for signs and symptoms of hypotension after initiating therapy.
Reports of ketoacidosis, a serious life-threatening
condition requiring urgent hospitalization, have been identified in
postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus
receiving sodium glucose cotransporter-2 (SGLT2) inhibitors, including
dapagliflozin. Fatal cases of ketoacidosis have been reported in patients
taking dapagliflozin. QTERNMET XR is not indicated for the treatment of
patients with type 1 diabetes mellitus [see INDICATIONS AND USAGE].
Patients treated with QTERNMET XR who present with signs
and symptoms consistent with severe metabolic acidosis should be assessed for
ketoacidosis regardless of presenting blood glucose levels as ketoacidosis
associated with QTERNMET XR may be present even if blood glucose levels are
less than 250 mg/dL. If ketoacidosis is suspected, QTERNMET XR should be
discontinued, the patient should be evaluated and prompt treatment should be
instituted. Treatment of ketoacidosis may require insulin, fluid and
In many of the postmarketing reports for dapagliflozin,
and particularly in patients with type 1 diabetes, the presence of ketoacidosis
was not immediately recognized and the institution of treatment was delayed
because the presenting blood glucose levels were below those typically expected
for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at
presentation were consistent with dehydration and severe metabolic acidosis and
included nausea, vomiting, abdominal pain, generalized malaise, and shortness
of breath. In some but not all cases, factors predisposing to ketoacidosis such
as insulin dose reduction, acute febrile illness, reduced caloric intake due to
illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g.,
type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol
abuse were identified.
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. In
patients treated with QTERNMET XR consider monitoring for ketoacidosis and
temporarily discontinuing QTERNMET XR in clinical situations known to
predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or
surgery) [see ADVERSE REACTIONS].
Acute Kidney Injury And Impairment In Renal Function
Dapagliflozin causes intravascular volume contraction [see
WARNINGS AND PRECAUTIONS] and can cause renal impairment [see ADVERSE
REACTIONS]. There have been postmarketing reports of acute kidney injury,
some requiring hospitalization and dialysis, in patients receiving
dapagliflozin; some reports involved patients younger than 65 years of age.
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 any setting of reduced oral intake (such as acute illness or fasting) or
fluid losses (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.
Dapagliflozin increases serum creatinine and decreases
eGFR. Elderly patients and patients with impaired renal function may be more
susceptible to these changes. Adverse reactions related to renal function can
occur after initiating QTERNMET XR [see ADVERSE REACTIONS]. 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 [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS
and Use In Specific Populations].
Urosepsis And Pyelonephritis
There have been postmarketing reports of serious urinary
tract infections including urosepsis and pyelonephritis requiring
hospitalization 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].
Hypoglycemia With Concomitant Use Of Insulin Or Insulin
Insulin and insulin secretagogues, such as sulfonylureas,
are known to cause hypoglycemia. Dapagliflozin, and saxagliptin can
individually increase the risk of hypoglycemia when combined with insulin or an
insulin secretagogue. Hypoglycemia does not occur in patients receiving
metformin alone under usual circumstances of use but could occur during
concomitant use with other glucose-lowering agents. Therefore, a lower dose of
insulin or insulin secretagogue may be required to reduce the risk of hypoglycemia
when these agents are used in combination with QTERNMET XR [see ADVERSE
Necrotizing Fasciitis Of The Perineum (Fournier’s
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 dapagliflozin. Cases have been reported in females and
males. Serious outcomes have included hospitalization, multiple surgeries, and
Patients treated with QTERNMET XR 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 QTERNMET XR, closely monitor blood glucose
levels, and provide appropriate alternative therapy for glycemic control.
There have been postmarketing reports of serious
hypersensitivity reactions in patients treated with saxagliptin. These
reactions include anaphylaxis, angioedema and exfoliative skin conditions.
Onset of these reactions occurred within the first 3 months after initiation of
treatment with saxagliptin, with some reports occurring after the first dose.
If a serious hypersensitivity reaction is suspected, discontinue QTERNMET XR,
treat per standard of care, and monitor until signs and symptoms are resolved.
Assess for other potential causes for the event. Institute alternative
treatment for diabetes.
Use caution in a patient with a history of angioedema to
another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether
such patients will be predisposed to angioedema with saxagliptin.
Vitamin B12 Concentrations
In controlled clinical trials of metformin of 29-week
duration, a decrease to subnormal levels of previously normal serum vitamin B12
levels, without clinical manifestations, was observed in approximately 7% of
patients. This decrease, possibly due to interference with B12 absorption from
the B12-intrinsic factor complex is, however, very rarely associated with
anemia and appears to be rapidly reversible with discontinuation of metformin
or vitamin B12 supplementation. Measurement of hematologic parameters on an
annual basis is advised in patients on QTERNMET XR and any apparent
abnormalities should be appropriately investigated and managed.
Certain individuals (those with inadequate vitamin B12 or
calcium intake or absorption) appear to be predisposed to developing subnormal
vitamin B12 levels. In these patients, routine serum vitamin B12 measurements
at 2-to 3-year intervals may be useful.
Genital Mycotic Infections
Dapagliflozin increases the risks of genital mycotic
infections. Patients with a history of genital mycotic infections were more
likely to develop genital mycotic infections [see ADVERSE REACTIONS].
Monitor and treat appropriately.
Increases In Low-Density Lipoprotein Cholesterol (LDL–C)
Increases in LDL–C can occur with dapagliflozin [see ADVERSE
REACTIONS]. Monitor LDL-C and treat per standard of care after initiating
Across 22 clinical studies for dapagliflozin, newly
diagnosed cases of bladder cancer were reported in 10/6045 patients (0.17%)
treated with dapagliflozin and 1/3512 patient (0.03%) treated with
placebo/comparator. After excluding patients in whom exposure to study drug was
less than one year at the time of diagnosis of bladder cancer, there were 4
cases with dapagliflozin and no cases with placebo/comparator. Bladder cancer
risk factors and hematuria (a potential indicator of pre-existing tumors) were
balanced between treatment arms at baseline. There were too few cases to
determine whether the emergence of these events is related to dapagliflozin.
There are insufficient data to determine whether
dapagliflozin has an effect on pre-existing bladder tumors. Consequently,
QTERNMET XR should not be used in patients with active bladder cancer. In
patients with prior history of bladder cancer, the benefits of glycemic control
versus unknown risks for cancer recurrence with QTERNMET XR should be
Severe And Disabling Arthralgia
There have been postmarketing reports of severe and
disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of
symptoms following initiation of drug therapy varied from one day to years.
Patients experienced relief of symptoms upon discontinuation of the medication.
A subset of patients experienced a recurrence of symptoms restarting the same
drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible
cause for severe joint pain and discontinue drug if appropriate [see ADVERSE
Postmarketing cases of bullous pemphigoid requiring
hospitalization have been reported with DPP-4 inhibitor use. In reported cases,
patients typically recovered with topical or systemic immunosuppressive
treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report
development of blisters or erosions while receiving QTERNMET XR. If bullous
pemphigoid is suspected, QTERNMET XR should be discontinued and referral to a dermatologist
should be considered for diagnosis and appropriate treatment.
There have been no clinical studies establishing
conclusive evidence of macrovascular risk reduction with QTERNMET XR.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
- Inform patients of the risks of lactic acidosis due to
the metformin component and its symptoms and conditions that predispose to its
development [see WARNINGS AND PRECAUTIONS]. Advise patients to
discontinue QTERNMET XR immediately and to promptly notify their healthcare
provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence,
dizziness, slow or irregular heartbeat, sensation of feeling cold (especially
in the extremities), or other nonspecific symptoms occur. Gastrointestinal
symptoms are common during initiation of metformin treatment and may occur
during initiation of QTERNMET XR therapy; however, inform patients to consult
their physician if they develop unexplained symptoms. Although gastrointestinal
symptoms that occur after stabilization are unlikely to be drug related, such
an occurrence of symptoms should be evaluated to determine if it may be due to
lactic acidosis or other serious disease.
- Counsel patients against excessive alcohol intake while
receiving QTERNMET XR.
- Inform patients about the importance of regular testing
of renal function and hematological parameters when receiving treatment with
- Instruct patients to inform their healthcare provider
that they are taking QTERNMET XR prior to any surgical or radiological
procedure, as temporary discontinuation of QTERNMET XR may be required until
renal function has been confirmed to be normal [see WARNINGS AND PRECAUTIONS].
- Inform patients that acute pancreatitis has been reported
during postmarketing use of saxagliptin. Inform patients that persistent severe
abdominal pain, sometimes radiating to the back, which may or may not be
accompanied by vomiting, is the hallmark symptom of acute pancreatitis [see WARNINGS
- Instruct patients to promptly discontinue QTERNMET XR and
contact their healthcare provider if persistent severe abdominal pain occurs.
- Inform patients of the signs and symptoms of heart
failure. Instruct patients to contact their healthcare provider as soon as
possible if they experience symptoms of heart failure, including increasing
shortness of breath, rapid increase in weight or swelling of the feet [see WARNINGS
- Inform patients that symptomatic hypotension may occur
with QTERNMET XR 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
- Inform patients that ketoacidosis is a serious
life-threatening condition. Cases of ketoacidosis have been reported during use
of dapagliflozin. 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 advice immediately [see WARNINGS AND
Acute Kidney Injury
- Inform patients that acute kidney injury has been
reported during use of dapagliflozin. Advise patients to seek medical advice
immediately if they have reduced oral intake (due to acute illness or fasting)
or increased fluid losses (due to vomiting, diarrhea, or excessive heat
exposure), as it may be appropriate to temporarily discontinue QTERNMET XR use
in those settings [see WARNINGS AND PRECAUTIONS].
Serious Urinary Tract Infections
- Inform patients of the potential for urinary tract
infections, which may be serious. Inform them of the symptoms of urinary tract
infections and advise them to seek medical advice if such symptoms occur [see WARNINGS
Necrotizing Fasciitis Of The Perineum (Fournier’s
- Inform patients that necrotizing infections of the
perineum (Fournier's gangrene) have occurred with dapagliflozin, a component of
QTERNMET XR. 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].
- Inform patients that serious hypersensitivity reactions
(e.g., anaphylaxis, angioedema, urticaria, and exfoliative skin conditions)
have been reported with dapagliflozin and saxagliptin, components of QTERNMET
XR. Symptoms of these allergic reactions include: rash, skin flaking or peeling,
urticaria, swelling of the skin, or swelling of the face, lips, tongue, and
throat that may cause difficulty in breathing or swallowing [see WARNINGS
- Advise patients to immediately report any signs or
symptoms suggesting allergic reaction, angioedema, or exfoliative skin
conditions, and stop taking QTERNMET XR and seek medical advice promptly.
Genital Mycotic Infections In Females (e.g.,
- 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].
Genital Mycotic Infections In Males (e.g., Balanitis)
- Inform male patients that yeast infections of the penis
(e.g., balanitis or balanoposthitis) may occur, especially in patients with
prior history. 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
- Inform patients to promptly report any signs of
macroscopic hematuria or other symptoms potentially related to bladder cancer [see
WARNINGS AND PRECAUTIONS].
Severe And Disabling Arthralgia
- Inform patients that severe and disabling joint pain may
occur with this class of drugs. The time to onset of symptoms can range from
one day to years. Instruct patients to seek medical advice if severe joint pain
occurs [see WARNINGS AND PRECAUTIONS].
- Inform patients that bullous pemphigoid may occur with
QTERNMET XR. Instruct patients to seek medical advice if blisters or erosions
occur [see WARNINGS AND PRECAUTIONS].
- Advise pregnant patients of the potential risk to a fetus
with treatment with QTERNMET XR. Instruct patients to immediately inform their
healthcare provider if pregnant or planning to become pregnant [see Use In
- Advise patients that use of QTERNMET XR is not
recommended while breastfeeding [see Use In Specific Populations].
Females And Males Of Reproductive Potential
- Inform female patients that treatment with metformin may
result in an unintended pregnancy in some premenopausal anovulatory females due
to its effect on ovulation [see Use In Specific Populations].
- Inform patients that due to its mechanism of action,
patients taking QTERNMET XR will test positive for glucose in their urine.
- Instruct patients that QTERNMET XR 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
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No animal studies have been conducted with the combined
products in QTERNMET XR to evaluate carcinogenesis, mutagenesis or impairment
of fertility. The following data are based on the findings in the studies with
dapagliflozin and saxagliptin individually.
Carcinogenicity was evaluated in 2-year studies conducted
in CD-1 mice and Sprague-Dawley rats. Dapagliflozin did not increase the
incidence of tumors in mice dosed orally at 5, 15, and 40 mg/kg/day in males
and 2, 10, and 20 mg/kg/day in females (exposure less than or equal to 72-times
(males) and 105-times (females) the 10 mg/day clinical dose, based on
AUC). Dapagliflozin did not increase the incidence of tumors in rats (both
males and females) dosed orally at 0.5, 2, and 10 mg/kg/day (exposure less than
or equal to 131-times (males) and 186-times (females) the clinical dose
of 10 mg/day, based on AUC).
Dapagliflozin was not mutagenic with or without metabolic
activation in the Ames assay. Dapagliflozin was mutagenic in a series of in
vitro clastogenicity assays at concentrations greater than or equal to 100
micrograms per mL but not without metabolic activation. Dapagliflozin was not
mutagenic or clastogenic in a series of in vivo studies evaluating micronuclei
or DNA repair in rats at exposure multiples greater than 2100-times the
Impairment Of Fertility
Dapagliflozin had no effects on the ability of rats to
mate and sire, maintain a litter, or early embryonic development at exposure
multiples less than or equal to 1708-and 998-times the maximum recommended
human doses of 10 mg/day (based on AUC) in males and females, respectively.
Carcinogenicity was evaluated in 2-year studies conducted
in CD-1 mice and Sprague-Dawley rats. Saxagliptin did not increase the
incidence of tumors in mice dosed orally at 50, 250, and 600 mg/kg up to
870-times (males) and 1165-times (females) the 5 mg/day clinical dose, based on
AUC. Saxagliptin did not increase the incidence of tumors in rats dosed orally
at 25, 75, 150, and 300 mg/kg up to 355-times (males) and 2217-times (females)
the 5 mg/day clinical dose, based on AUC.
Saxagliptin was not mutagenic or clastogenic in a battery
of genotoxicity tests (Ames bacterial mutagenesis, human and rat lymphocyte
cytogenetics, rat bone marrow micronucleus and DNA repair assays). The active
metabolite of saxagliptin was not mutagenic in an Ames bacterial assay.
Impairment Of Fertility
Saxagliptin administered to rats had no effect on
fertility or the ability to maintain a litter at exposures up to 603-times and
776-times the 5 mg clinical dose in males and females, based on AUC.
Long-term carcinogenicity studies have been performed in
rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at
doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These
doses are both approximately 4 times the maximum recommended human daily dose
of 2000 mg based on body surface area comparisons. No evidence of
carcinogenicity with metformin was found in either male or female mice.
Similarly, there was no tumorigenic potential observed with metformin in male
rats. There was, however, an increased incidence of benign stromal uterine
polyps in female rats treated with 900 mg/kg/day.
There was no evidence of a mutagenic potential of
metformin in the following in vitro tests: Ames test (S. typhimurium), gene
mutation test (mouse lymphoma cells), or chromosomal aberrations test (human
lymphocytes). Results in the in vivo mouse micronucleus test were also
Impairment Of Fertility
Fertility of male or female rats was unaffected by
metformin when administered at doses as high as 600 mg/kg/day, which is
approximately 3-times the maximum recommended human daily dose based on body surface
Use In Specific Populations
Based on animal data showing adverse renal effects, from
dapagliflozin, QTERNMET XR is not recommended during the second and third
trimesters of pregnancy.
The limited available data with QTERNMET XR or components
(dapagliflozin and saxagliptin) in pregnant women are not sufficient to
determine a drug-associated risk for major birth defects or miscarriage.
Published studies with metformin use during pregnancy have not reported a clear
association with metformin and major birth defect or miscarriage risk [see Data].
There are risks to the mother and fetus associated with poorly controlled
diabetes in pregnancy [see Clinical Considerations].
In animal studies, adverse renal pelvic and tubular
dilatations, that were not fully reversible, were observed in rats when
dapagliflozin (a component of QTERNMET XR) was administered during a period of
renal development corresponding to the late second and third trimesters of
human pregnancy, at all doses tested; the lowest of which provided an exposure
15-times the 10 mg clinical dose [see Data].
No adverse developmental effects were observed when
saxagliptin was administered to pregnant rats and rabbits [see Data].
The estimated background risk of major birth defects is 6
to 10% in women with pre-gestational diabetes with an HbA1c greater than 7% and
has been reported to be as high as 20 to 25% in women with an 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 to 4% and 15 to 20%, respectively.
Disease-Associated Maternal And/Or Embryo-Fetal Risk
Poorly controlled diabetes in pregnancy increases the
maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions,
preterm delivery and delivery complications. Poorly controlled diabetes
increases the fetal risk for major birth defects, stillbirth, and macrosomia
Published data from post-marketing studies have not
reported a clear association with metformin and major birth defects,
miscarriage, or adverse maternal or fetal outcomes when metformin was used
during pregnancy. However, these studies cannot definitely establish the
absence of any metformin-associated risk because of methodological limitations,
including small sample size and inconsistent comparator groups.
Dapagliflozin dosed directly to juvenile rats from
postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day,
increased kidney weights and increased the incidence of renal pelvic and
tubular dilatations at all dose levels. Exposure at the lowest dose was
15-times the 10 mg clinical dose (based on AUC). The renal pelvic and tubular
dilatations observed in juvenile animals did not fully reverse within a 1-month
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.
In 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).
Saxagliptin And Metformin
Saxagliptin and metformin coadministered to pregnant rats
and rabbits during the period of organogenesis did not result in adverse
developmental effects considered clinically relevant in either species. Doses
tested in rats provided exposure up to 100-and 10-times clinical exposure, and
doses tested in rabbits provided exposure up to 249-and 1-times clinical
exposure relative to the clinical dose of 5 mg saxagliptin and 2000 mg
metformin. Minor skeletal abnormalities associated with maternal toxicity were
observed in rats. In rabbits, coadministration was poorly tolerated in a subset
of mothers (12 of 30), resulting in death, moribundity, or abortion. However,
among surviving mothers with evaluable litters, maternal toxicity was limited
to marginal reductions in body weight over the course of gestation days 21 to
29, associated with fetal body weight decrements of 7%, and a low incidence of
delayed ossification of the fetal hyoid bone.
In embryo-fetal development studies, saxagliptin was
administered to pregnant rats and rabbits during the period of organogenesis,
corresponding to the first trimester of human pregnancy. No adverse
developmental effects were observed in either species at exposures 1503-and
152-times the 5 mg clinical dose in rats and rabbits, respectively, based on
AUC. Saxagliptin crosses the placenta into the fetus following dosing in
In a prenatal and postnatal development study, no adverse
developmental effects were observed in maternal rats administered saxagliptin
from gestation Day 6 through lactation Day 21 at exposures up to 470-times the
5 mg clinical dose, based on AUC.
Metformin was not teratogenic in rats and rabbits at doses
up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the
maximum recommended human daily dose of 2000 mg based on body surface area
comparisons for rats and rabbits, respectively. Determination of fetal
concentrations demonstrated a partial placental barrier to metformin.
There is limited information regarding the presence of
QTERNMET XR or its components (dapagliflozin, saxagliptin, and metformin) in
human milk, the effects on the breastfed infant, or the effects on milk
production. Limited published studies report that metformin is present in human
milk [see Data].
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 QTERNMET XR is not recommended while
Dapagliflozin was present at a milk/plasma ratio of 0.49,
indicating that dapagliflozin and its metabolites are transferred into milk at
a concentration that is approximately 50% of that in maternal plasma. Juvenile
rats directly exposed to dapagliflozin showed a risk to the developing kidney
(renal pelvic and tubular dilatations) during maturation.
Saxagliptin is secreted in the milk of lactating rats at
approximately a 1:1 ratio with plasma drug concentrations.
Published clinical lactation studies report that
metformin is present in human milk which resulted in infant doses approximately
0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio
ranging between 0.13 and 1. However, the studies were not designed to
definitely establish the risk of use of metformin during lactation because of
small sample size and limited adverse event data collected in infants.
Females And Males Of Reproductive Potential
Discuss the potential for unintended pregnancy with
premenopausal women as therapy with metformin may result in ovulation in some
Safety and effectiveness of QTERNMET XR in patients under
18 years of age have not been established.
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 [see WARNINGS
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 safety and efficacy
studies of dapagliflozin. 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
related to volume depletion and renal impairment or failure compared to
patients treated with placebo [see WARNINGS AND PRECAUTIONS].
In the seven, double-blind, controlled clinical safety
and efficacy trials of saxagliptin, a total of 4751 (42.0%) of the 11,301
patients randomized to saxagliptin were 65 years and over, and 1210 (10.7%)
were 75 years and over. No overall differences in safety or effectiveness were
observed between subjects ≥65 years old and younger subjects. While this
clinical experience has not identified differences in responses between the
elderly and younger patients, greater sensitivity of some older individuals cannot
be ruled out.
Controlled clinical studies of metformin did not include
sufficient numbers of elderly patients to determine whether they respond
differently from younger patients, although other reported clinical experience
has not identified differences in responses between the elderly and young
patients. Metformin is known to be substantially excreted by the kidney. 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 [see CONTRAINDICATIONS, WARNINGS
AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
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 [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS and WARNINGS
In clinical studies dapagliflozin was associated with
increases in serum creatinine and decreases in eGFR [see ADVERSE REACTIONS].
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.
Metformin is substantially excreted by the kidney, and
the risk of metformin accumulation and lactic acidosis increases with the
degree of renal impairment.
Use of metformin in patients with hepatic impairment has
been associated with some cases of lactic acidosis. QTERNMET XR is not
recommended in patients with hepatic impairment [see CLINICAL PHARMACOLOGY].