Approved Drug Label (PDF)
5
Warnings and Precautions
5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
Section title revised
Additions and revisions
underlined:
Insulin secretagogues and insulin
are known to cause hypoglycemia. The risk of hypoglycemia is increased when JENTADUETO is used in combination with an insulin
secretagogue (e.g., sulfonylurea) or insulin [see Adverse Reactions (6.1)]. Therefore, a lower dose of the
insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in
combination with JENTADUETO.
6
Adverse Reactions
Additions and revisions
underlined:
The following serious adverse
reactions are described below or elsewhere
in the prescribing information:
Lactic Acidosis [see Warnings
and Precautions (5.1)]
Pancreatitis [see Warnings and Precautions (5.2)]
Hypoglycemia with Concomitant Use with Insulin
and Insulin Secretagogues [see Warnings and Precautions (5.3)]
Hypersensitivity Reactions [see Warnings
and Precautions (5.4)]
Vitamin B12 Deficiency [see Warnings
and Precautions (5.5)]
Severe and Disabling
Arthralgia [see Warnings and Precautions (5.6)]
Bullous Pemphigoid [see Warnings
and Precautions (5.7)]
Heart Failure [see Warnings and Precautions (5.8)]
6.1 Clinical Trials Experience
Metformin
The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.
7
Drug Interactions
Newly added table of drug
interactions
8
Use in Specific Populations
8.1 Pregnancy
Additions and revisions
underlined:
Linagliptin
No adverse developmental outcome
was observed when linagliptin was administered to pregnant Wistar Han rats and
Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and
150 mg/kg/day, respectively. These doses represent approximately 943-times (rats)
and 1943-times (rabbits) the 5 mg maximum
clinical dose, based on exposure. No adverse functional, behavioral, or
reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from
gestation day 6 to lactation day 21 at a dose 49-times the maximum
recommended human dose, based on exposure.
Linagliptin crosses
the placenta into the fetus following oral dosing in pregnant rats and rabbits.
Metformin Hydrochloride
Metformin hydrochloride did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits at doses up to 600 mg/kg/day during
the period of organogenesis. This
represents an exposure
of approximately 2- and 6-times
a clinical dose of 2000 mg, based on body surface area (mg/m2) for rats
and rabbits, respectively.
8.2 Lactation
Additions and revisions
underlined:
Risk Summary
There is limited information regarding the presence
of JENTADUETO or its components (linagliptin or metformin) in
human milk, the effects on the breastfed infant, or the effects on milk
production.
8.4 Pediatric Use
Additions and revisions
underlined:
Safety and effectiveness of JENTADUETO have not been established in pediatric patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
Additions and revisions
underlined:
Lactic Acidosis
Inform patients of the risks of lactic acidosis due to
metformin, its symptoms, and conditions that predispose to its development.
Advise patients to discontinue JENTADUETO immediately and to notify their healthcare
provider promptly if unexplained hyperventilation, malaise, myalgia,
unusual somnolence, or other nonspecific symptoms occur. Counsel patients
against excessive alcohol intake and inform patients about importance of
regular testing of renal function while receiving JENTADUETO. Instruct patients
to inform their healthcare provider that they are taking JENTADUETO prior to
any surgical or radiological procedure, as temporary discontinuation may be
required until renal function has been confirmed to be normal [see Warnings and
Precautions (5.1)].
Vitamin B12 Deficiency
Inform
patients about importance of regular hematological parameters while
receiving JENTADUETO [see Warnings and Precautions (5.5)].
Patients of Reproductive Potential
Inform patients that treatment with metformin may result in ovulation
in some premenopausal anovulatory patients, which may lead to unintended
pregnancy [see Use in Specific Populations (8.3)].
Missed Dose
Instruct patients to take JENTADUETO only as prescribed. If
a dose is missed, it should be taken as soon as the patient remembers.
Advise patients not to double their next dose.
Medication Guide
Additions and revisions
underlined:
Allergic (hypersensitivity) reactions. Serious allergic
reactions have happened in people who are taking JENTADUETO. Symptoms may
include:
o swelling of your face, lips, tongue, throat, and
other areas on your skin
Before you start taking JENTADUETO, tell your healthcare
provider if you have ever had heart failure or have problems with your kidneys.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.4
Use with
Medications Known to Cause Hypoglycemia
(Additions and/or revisions underlined)
Insulin secretagogues and insulin
are known to cause hypoglycemia. The use of linagliptin in combination with an
insulin secretagogue (e.g., sulfonylurea) or insulin was associated with
a higher rate of hypoglycemia compared with placebo in clinical trials. Metformin
may increase the risk of hypoglycemia when combined with insulin and/or an
insulin secretagogue. Therefore, a lower dose of the insulin secretagogue or
insulin may be required to reduce the risk of hypoglycemia when used in
combination with JENTADUETO.
5.5 Hypersensitivity Reactions
(Additions and/or
revisions underlined)
There have been postmarketing
reports of serious hypersensitivity reactions in patients treated with
linagliptin (one of the components of JENTADUETO). These reactions include
anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these
reactions occurred predominantly within the first 3 months after
initiation of treatment with linagliptin, with some reports occurring after the
first dose. If a serious hypersensitivity reaction is suspected, discontinue
JENTADUETO, assess for other potential causes for the event, and institute
alternative treatment for diabetes.
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or
revisions underlined)
Hypoglycemia
Linagliptin/Metformin
In a 24-week
factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects
treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with
metformin, and 1 (1.4%) of 72 subjects treated with placebo. The incidence
of hypoglycemia with plasma glucose <54 mg/dL was 8.1% in the linagliptin
group (N=792) compared to 5.3% in the placebo group (N=263) when administered
in combination with metformin and sulfonylurea in a 24-week study.
Linagliptin
The incidence of severe hypoglycemia
(requiring assistance) was 1.7% in the linagliptin group (N=631) compared to
1.1% in the placebo group (N=630) when administered in combination with basal
insulin in a 52 week study.
Laboratory Tests
Linagliptin
Increase in Uric Acid: Changes
in laboratory values that occurred more frequently in the linagliptin group and
greater than or equal to 1% more than in the placebo group were increases in uric acid (1.3% in the
placebo group, 2.7% in the linagliptin group).
Increase in
Lipase: In a placebo-controlled clinical
trial with linagliptin in type 2 diabetes mellitus patients with micro- or
macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline
to 24 weeks was observed in the linagliptin arm compared to a mean decrease of
2% in the placebo arm. Lipase levels above 3 times upper limit of normal were
seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms,
respectively.
Increase in Amylase: In a cardiovascular safety study comparing linagliptin
versus glimepiride in patients with type 2 diabetes mellitus, amylase levels
above 3 times upper limit of normal were seen in 1.0% compared to 0.5% of
patients in the linagliptin and glimepiride arms, respectively.
The clinical significance of
elevations in lipase and amylase with linagliptin is unknown in the absence of
potential signs and symptoms of pancreatitis.
8
Use in Specific Populations
8.5 Geriatric
Use
Linagliptin is minimally
excreted by the kidney; however, metformin is substantially excreted by the
kidney.
Linagliptin
In
the 15 type 2 diabetes studies
with linagliptin, 1085 linagliptin-treated patients were 65 years
of age and older (including 131 linagliptin-treated patients 75
years of age and older). Of these 15 studies, 12 were double-blind
placebo-controlled. In these 12 studies, 591 linagliptin-treated patients were
65 years of age and older (including 82 linagliptin-treated patients 75 years
of age and older). In these linagliptin studies, no overall differences in
safety or effectiveness of linagliptin were observed between geriatric
patients and younger adult patients.
Approved Drug Label (PDF)
4
Contraindications
(Additions and/or revisions are underlined)
![]()
JENTADUETO is contraindicated in patients with:
Severe renal impairment (eGFR below 30 mL/min/1.73 m^2)
Acute or chronic metabolic
acidosis, including
diabetic ketoacidosis
Hypersensitivity to linagliptin, metformin, or any of the
excipients in JENTADUETO, reactions such as anaphylaxis, angioedema, exfoliative
skin conditions, urticaria, or
bronchial hyperreactivity have
occurred with linagliptin
5
Warnings and Precautions
5.2 Pancreatitis
(Additions and/or revisions
are underlined)
Acute pancreatitis, including fatal pancreatitis, has been reported in
patients treated with linagliptin. In the
CARMELINA trial, acute pancreatitis was reported in 9 (0.3%) patients
treated with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients treated
with linagliptin in the
CARMELINA trial
had acute pancreatitis with a fatal outcome. There
have been postmarketing reports of acute pancreatitis,
including fatal
pancreatitis, in patients treated with linagliptin.
Take
careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue
JENTADUETO 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 JENTADUETO.
5.4 Use with Medications Known to Cause Hypoglycemia
(Additions and/or revisions
are underlined)
Insulin secretagogues and
insulin are known to cause hypoglycemia. The use of linagliptin in combination
with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher
rate of hypoglycemia compared with placebo in a clinical trial. The use of
linagliptin in combination with insulin in subjects with severe renal
impairment was associated with a higher rate of hypoglycemia. Metformin may
increase the risk of hypoglycemia when combined with insulin and/or an insulin
secretagogue. Therefore, a lower dose of the insulin
secretagogue or insulin may be required to
reduce the risk of hypoglycemia
when used in
combination with JENTADUETO.
5.6 Vitamin B12 Levels
(Additions and/or revisions
are underlined)
In controlled, 29-week clinical trials of metformin, a decrease to subnormal
levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in
approximately 7% of
metformin-treated patients. Such decrease, possibly due to interference
with B12
absorption from the B12 -intrinsic factor complex, may be associated with anemia
or neurologic manifestations. This risk may be
more relevant
to
patients receiving
long-term treatment
with
metformin, and
adverse hematologic and neurologic reactions have been reported postmarketing. The decrease in vitamin B12 levels appears
to be rapidly
reversible with
discontinuation of metformin or
vitamin B12 supplementation.
Measurement of hematologic parameters on an
annual basis and routine serum vitamin B12 measurement at 2- to
3-year intervals is
advised in patients
on JENTADUETO 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.
5.8 Bullous Pemphigoid
(Additions and/or revisions
are underlined)
Bullous pemphigoid
was reported in 7
(0.2%) patients
treated with linagliptin compared
to none in patients treated with placebo in
the CARMELINA trial,
and 3 of these patients were hospitalized due to bullous pemphigoid. 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 JENTADUETO. If
bullous pemphigoid is
suspected, JENTADUETO should
be
discontinued and referral
to a dermatologist should
be considered for
diagnosis and
appropriate treatment.
6
Adverse Reactions
(Additions
and/or revisions are underlined)
The following serious adverse
reactions are described
below or elsewhere in the prescribing information:
Lactic Acidosis
Pancreatitis
Heart Failure
Use with Medications Known to
Cause Hypoglycemia
Hypersensitivity Reactions
Vitamin B12 Levels
Severe and Disabling
Arthralgia
Bullous Pemphigoid
6.2 Postmarketing Experience
(Additions and/or revisions
are underlined)
The following 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.
Linagliptin
Acute pancreatitis, including fatal pancreatitis
Hypersensitivity reactions including
anaphylaxis, angioedema, and exfoliative skin
conditions
Severe and disabling arthralgia
Bullous pemphigoid
Rash
Mouth
ulceration, stomatitis
Rhabdomyolysis
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or revisions
are underlined)
Clinical
Considerations
Disease-associated maternal and/or embryo/fetal risk
Poorly controlled diabetes
in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous
abortions, preterm delivery,
and
delivery
complications.
Poorly controlled diabetes
increases the fetal risk for major
birth defects, stillbirth, and macrosomia-
related morbidity.
8.6 Renal Impairment
(Additions and/or revisions
are underlined)
Metformin is substantially excreted by the
kidney, and the
risk of metformin accumulation
and lactic acidosis increases
with the degree of renal impairment. JENTADUETO
is contraindicated in
severe renal impairment, patients
with
an estimated glomerular filtration rate
(eGFR) below 30 mL/min/1.73 m^2 .
If JENTADUETO
is discontinued due to
evidence of renal impairment, linagliptin may be
continued as a single
entity tablet at the same total daily dose
of 5 mg. No dose adjustment of linagliptin is recommended in patients with renal impairment.
In the linagliptin treatment arm of the CARMELINA trial,
2200 (63%) patients
had renal impairment (eGFR <60 mL/min/1.73m2). Approximately 20% of the population had eGFR greater than or equal to 45 to <60 mL/min/1.73 m2, 28% of the population had eGFR greater
than or equal to 30 to <45 mL/min/1.73 m2 and 15% had eGFR <30
mL/min/1.73 m2. The
overall incidence of adverse
reactions were generally similar between the linagliptin
and placebo treatment arms.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions
are underlined)
Bullous
Pemphigoid
Inform patients that
bullous
pemphigoid has been reported during use of
linagliptin.
Instruct patients to seek medical
advice if
blisters or erosions
occur.
Pregnancy
Inform female
patients that treatment with metformin may result in an
unintended pregnancy in some premenopausal
anovulatory females due to its effect on ovulation.
Missed Dose
Instruct
patients to take
JENTADUETO only as prescribed. If a dose is
missed, advise patients not to double their next dose.
Medication Guide Jentadueto
(Extensive
changes; please refer to labeling)
Approved Drug Label (PDF)
5
Warnings and Precautions
5.3 Heart Failure
(Newly added subsection)
An association
between DPP-4 inhibitor treatment and heart failure has been observed in
cardiovascular outcomes trials for two other members of the DPP-4 inhibitor
class. These trials evaluated patients with type 2 diabetes mellitus and
atherosclerotic cardiovascular disease.
Consider the risks
and benefits of JENTADUETO prior to initiating treatment in patients at risk
for heart failure, such as those with a prior history of heart failure and a
history of renal impairment, and observe these patients for signs and symptoms
of heart failure during therapy. Advise patients of the characteristic symptoms
of heartfailure and to immediately report such symptoms. If heart failure
develops, evaluate and manage according to current standards of care and
consider discontinuation of JENTADUETO.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions are underlined)
Heart Failure
Inform patients
of the signs and symptoms of heart failure. Before initiating JENTADUETO,
patients should be asked about a history of heart failure or other risk factors
for heart failure including moderate to severe renal impairment. 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.
MEDICATION GUIDE
(Additions and/or revisions are underlined)
What is the most important information I
should know about JENTADUETO?
Serious side effects can happen in people
taking JENTADUETO, including:
3. Heart failure. Heart failure means that your heart does not
pump blood well enough.
Before you start taking JENTADUETO, tell your doctor if you have ever had heart
failure or have problems with your kidneys. Contact your doctor right away if
you have any of the following symptoms:
- increasing shortness of breath or trouble breathing, especially
when you lie down
- swelling or fluid retention, especially in the feet, ankles or
legs
- an unusually fast increase in weight
- unusual tiredness
These may be
symptoms of heart failure.
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions are underlined)
Laboratory Tests
Linagliptin
Increase in Uric Acid: Changes in laboratory values that occurred more
frequently in the linagliptin group and greater than or equal to 1% more than
in the placebo group were increases in uric acid (1.3% in the placebo
group, 2.7% in the linagliptin group).
Increase in Lipase: In a placebo-controlled clinical trial with linagliptin in type 2 diabetes mellitus
patients with micro- or macroalbuminuria, a mean increase of 30% in lipase
concentrations from baseline to 24 weeks was observed in the linagliptin arm
compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3
times upper limit of normal were seen in 8.2% compared to 1.7% patients in the
linagliptin and placebo arms, respectively.
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation
Labeling Rule (PLLR) conversion-additions and/or revisions are underlined)
Risk Summary
The limited data with
JENTADUETO and linagliptin use in pregnant women are not sufficient to inform a
JENTADUETO-associated or linagliptin-associated risk for major birth defects and
miscarriage. Published studies with metformin use during pregnancy have not
reported a clear association with metformin and major birth defect or
miscarriage risk. There are risks to
the mother and fetus associated with poorly controlled diabetes in pregnancy.
In animal reproduction
studies, no adverse developmental effects were observed when the combination of
linagliptin and metformin was administered to pregnant rats during
the period of organogenesis at doses similar to the maximum recommended
clinical dose, based on exposure.
The estimated background
risk of major birth defects is 6 to10% in women with pre-gestational diabetes
with a HbA1c>7 and has been reported to be as high as 20-25% in women with
HbA1c>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.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Poorly controlled diabetes
in pregnancy increases the maternal risk for diabetic ketoacidosis,
pre-eclampsia, and delivery complications. Poorly controlled diabetes increases
the fetal risk for major birth defects, still birth, and macrosomia-related
morbidity.
Data
Human Data
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.
Animal Data
Linagliptin and metformin,
the components of JENTADUETO, were coadministered to pregnant Wistar Han rats
during the period of organogenesis. No adverse developmental outcome was
observed at doses similar to the maximum recommended clinical dose, based on
exposure. At higher doses associated with maternal toxicity, the metformin component of the combination was
associated with an increased incidence of fetal rib and scapula malformations at
greater than or equal to 9-times a 2000 mg clinical dose, based on exposure.
Linagliptin
No adverse developmental
outcome was observed when linagliptin
was administered to pregnant Wistar Han rats and Himalayan rabbits during
the period of organogenesis at doses up to 240 mg/kg and 150 mg/kg,
respectively. These doses represent approximately 943 times (rats)
and 1943 times (rabbits) the 5 mg clinical dose, based on
exposure. No adverse functional, behavioral, or reproductive outcome was
observed in offspring following administration of linagliptin to
Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49 times the
5 mg clinical dose, based on exposure.
Metformin Hydrochloride
Metformin hydrochloride
did not cause adverse developmental effects when administered to
pregnant rabbits up to 600 mg/kg/day during the period of organogenesis.
This represents an exposure of approximately 6-times a clinical dose of
2000 mg, based on body surface area.
8.2 Lactation
(Pregnancy and Lactation
Labeling Rule (PLLR) conversion-Newly added subsection)
Risk Summary
There is no information
regarding the presence of JENTADUETO or linagliptin in human milk, the effects
on the breastfed infant, or the effects on milk production. However,
linagliptin is present in rat milk. Limited published studies report that
metformin is present in human milk [see
Data]. However, there is insufficient information to determine the effects
of metformin on the breastfed infant and no available information on the
effects of metformin on milk production. Therefore, the developmental and
health benefits of breastfeeding should be considered along with the mother’s
clinical need for JENTADUETO and any potential adverse effects on the breastfed
child from JENTADUETO or from the underlying maternal condition.
Data
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.
8.3 Females and Males of Reproductive Potential
(Pregnancy and Lactation
Labeling Rule (PLLR) conversion-Newly added subsection)
Discuss the potential for
unintended pregnancy with premenopausal women as therapy with metformin may
result in ovulation in some anovulatory women.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions are underlined)
Pregnancy
Inform female patients
that treatment with metformin may result in an unintended pregnancy in some
premenopausal anovulatory females due to its effect on ovulation.
MEDICATION GUIDE JENTADUETO® (JEN ta doo e' toe) (linagliptin and metformin hydrochloride) Tablets
(Additions and/or revisions
are underlined)
What should I tell my
doctor before using JENTADUETO? Before you take JENTADUETO, tell your doctor if
you:
• are a premenopausal
woman (before the “change of life”), who does not have periods regularly or at
all. Talk to your doctor about birth control choices while taking
JENTADUETO if you are not planning to become pregnant since JENTADUETO may
increase your chance of becoming pregnant. Tell your doctor right away if you
become pregnant while taking JENTADUETO.
Approved Drug Label (PDF)
Boxed Warning
(Additions and/or revisions are underlined)
WARNING: LACTIC ACIDOSIS
Postmarketing
cases of metformin-associated lactic acidosis have resulted in death,
hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated
lactic acidosis
is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias,
respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic
acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/Liter),
anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate
ratio; and metformin plasma levels generally greater than 5 mcg/mL.
Risk
factors for metformin-associated lactic acidosis include renal impairment, concomitant
use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age
65 years old or greater, having a radiological study with contrast, surgery and
other procedures, hypoxic states (e.g., acute congestive heart failure), excessive
alcohol intake, and hepatic impairment.
Steps
to reduce the risk of and manage metformin-associated lactic acidosis in these high
risk groups are provided in the full prescribing information.
If metformin-associated lactic acidosis is suspected,
immediately discontinue JENTADUETO and institute general supportive measures
in a hospital setting. Prompt hemodialysis
is recommended.
4
Contraindications
(Additions and/or revisions are underlined)
JENTADUETO is contraindicated
in patients with:
- Severe renal impairment (eGFR below 30 mL/min/1.73 m2)
5
Warnings and Precautions
5.1 Lactic Acidosis
(Additions and/or revisions are underlined)
Metformin
There have been postmarketing 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 (greater than 5
mmol/Liter), anion gap acidosis (without evidence of ketonuria or
ketonemia), and an increased lactate pyruvate ratio; metformin plasma levels
generally greater than 5 mcg/mL. Metformin decreases liver uptake of lactate
increasing lactate blood levels which may increase 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 JENTADUETO. In
JENTADUETO-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
clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis
has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of
lactic acidosis and if these symptoms occur instruct them to discontinue
JENTADUETO 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:
Renal Impairment: 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 based upon the patient’s renal function include:
- Before initiating JENTADUETO, obtain an estimated
glomerular filtration rate (eGFR).
- JENTADUETO is
contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2.
- Initiation of
JENTADUETO is not recommended in patients with eGFR between 30 – 45
mL/min/1.73 m2.
- Obtain an eGFR at least
annually in all patients taking JENTADUETO. In patients at increased risk
for the development of renal impairment (e.g., the elderly), renal
function should be assessed more frequently.
- In patients taking
JENTADUETO whose eGFR later falls below 45 mL/min/1.73 m2, assess the
benefit and risk of continuing therapy.
Drug Interactions: The concomitant use of
JENTADUETO 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. Therefore, consider more frequent monitoring of patients.
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.
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 JENTADUETO at the time of, or prior to, an iodinated contrast
imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; 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 JENTADUETO 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. JENTADUETO should be
temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States: 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 JENTADUETO.
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 JENTADUETO.
Hepatic Impairment: Patients with hepatic
impairment have developed cases of metformin-associated lactic acidosis. This
may be due to impaired lactate clearance resulting in higher lactate blood
levels. Therefore, avoid use of JENTADUETO in patients with clinical or
laboratory evidence of hepatic disease.
6
Adverse Reactions
6.2 Postmarketing Experience
(Additions and/or revisions are underlined)
Metformin
- Cholestatic, hepatocellular, and mixed hepatocellular liver injury
7
Drug Interactions
7.1 Drug Interactions with Metformin
(Additions and/or revisions are underlined)
Carbonic Anhydrase Inhibitors
…Consider more frequent monitoring of these patients.
Drugs that Reduce Metformin Clearance
Concomitant use of drugs that interfere with common renal
tubular transport systems involved in the renal elimination of metformin (e.g.,
organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE]
inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could
increase systemic exposure to metformin and may increase the risk for lactic
acidosis. Consider the benefits and risks of concomitant use.
Alcohol
…Warn patients against excessive alcohol intake while
receiving JENTADUETO.
7.3 Insulin Secretagogues or Insulin
(Newly added subsection)
Co-administration of JENTADUETO with an insulin
secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the
insulin secretagogue or insulin to reduce the risk of hypoglycemia.
8
Use in Specific Populations
8.5 Geriatric Use
(Additions and/or revisions are underlined)
Metformin
…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
(Revised subsection title; Additions and/or revisions are
underlined)
JENTADUETO is contraindicated in severe renal
impairment, patients with an estimated glomerular filtration rate (eGFR)
below 30 mL/min/1.73 m2.
8.7 Hepatic Impairment
(Revised subsection title; Additions and/or revisions are
underlined)
Use of metformin in patients with hepatic impairment
has been associated with some cases of lactic acidosis. JENTADUETO is not
recommended in patients with hepatic impairment.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(Additions and/or revisions are underlined)
What is the most important information I should know
about JENTADUETO? Serious side effects can happen in people taking JENTADUETO,
including:
1. Lactic acidosis…
- you have stomach
pains, nausea or vomiting
Most people who have had lactic acidosis with metformin
have other things that, combined with metformin, led to the lactic acidosis.
Tell your doctor if you have any of the following, because you have a higher
chance of getting lactic acidosis with JENTADUETO if you…
- have severe kidney problems
The best way to keep from having a problem with lactic
acidosis from metformin is to tell your doctor if you have any of the problems
in the list above. Your doctor may decide to stop your JENTADUETO for a while
if you have any of these things. JENTADUETO can have other serious side
effects. See “What are the possible side effect of JENTADUETO?”
Who should not take JENTADUETO? Do not take JENTADUETO
if you:
- have severe kidney
problems
What should I tell my doctor before using JENTADUETO? Before
you take JENTADUETO, tell your doctor if you:
- have severe kidney problems
- are going to get an injection
of dye or contrast agents for an x-ray procedure. JENTADUETO may need
to be stopped for a short time…
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