Approved Drug Label (PDF)
6
Adverse Reactions
6.2 Postmarketing Experience
Additions and/or revisions underlined
…
Hypersensitivity reactions including anaphylaxis,
angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin
conditions including Stevens-Johnson syndrome; hepatic enzyme elevations; acute
pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing
pancreatitis [see Indications and Usage
(1)]; worsening renal function, including acute renal failure (sometimes
requiring dialysis), and tubulointerstitial nephritis; severe and
disabling arthralgia; bullous
pemphigoid; constipation; vomiting;
headache; myalgia; pain in extremity; back pain; pruritus; mouth ulceration;
stomatitis; rhabdomyolysis.
Approved Drug Label (PDF)
Boxed Warning
5.4 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
(Additions and/or revisions
underlined)
When
JANUVIA was used in combination with insulin or insulin secretagogues (e.g.,
sulfonylurea), medications known to cause hypoglycemia, the incidence of
hypoglycemia was increased over that of placebo used in combination with a
sulfonylurea or with insulin. [See
Adverse Reactions (6.1).] Therefore, a lower dose of sulfonylurea or
insulin may be required to reduce the risk of hypoglycemia. [See Drug Interactions (7.1).]
6
Adverse Reactions
(Additions and/or revisions
underlined)
The following adverse
reactions are also discussed elsewhere in the labeling:
Pancreatitis [see Warnings and
Precautions (5.1)]
Heart Failure [see Warnings and
Precautions (5.2)]
Acute Renal Failure [see Warnings
and Precautions (5.3)]
Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
[see Warnings and Precautions (5.4)]
Hypersensitivity Reactions [see
Warnings and Precautions (5.5)]
Severe and Disabling Arthralgia [see
Warnings and Precautions (5.6)]
Bullous Pemphigoid [see Warnings
and Precautions (5.7)]
8
Use in Specific Populations
8.4 Pediatric Use
(Additions and/or revisions
underlined)
The safety and effectiveness of JANUVIA have not
been established in pediatric patients.
Three 20-week
double-blind, placebo-controlled studies each with 34-week extensions were
conducted to evaluate the efficacy and safety of sitagliptin in 410 pediatric
patients aged 10 to 17 years with inadequately controlled type 2
diabetes, with or without insulin therapy (HbA1c 6.5-10% for patients not on
insulin, HbA1c 7-10% for patients on insulin). At study entry, patients in
study 1 were not treated with oral antihyperglycemic agents; patients in
studies 2 and 3 were on maximally tolerated metformin therapy. The primary
efficacy endpoint was the change from baseline in HbA1c after 20 weeks of
therapy. The pre-specified primary efficacy analyses included data from study 1
and pooled data from studies 2 and 3, regardless of glycemic rescue or
treatment discontinuation.
In both
efficacy analyses, the effect of treatment with sitagliptin was not
significantly different from placebo. In study 1, the mean baseline HbA1c was
7.5%, and 12% of patients were on insulin therapy. At week 20, the change from
baseline in HbA1c in patients treated with JANUVIA (N=95) was 0.06% compared to
0.23% in patients treated with placebo (N=95), a difference of -0.17% (95% CI:
-0.62, 0.28). In studies 2 and 3, the mean baseline HbA1c was 8.0%, 15% of
patients were on insulin and 72% were on metformin HCl doses of greater than
1,500 mg daily. At week 20, the change from baseline in HbA1c in patients
treated with sitagliptin (N=107) was -0.23% compared to 0.09% in patients
treated with placebo (N=113), a difference of -0.33% (95% CI: -0.70, 0.05).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions
underlined)
Hypoglycemia
Inform patients
that the incidence of hypoglycemia is increased when JANUVIA is added to a
sulfonylurea or insulin. Explain to patients receiving JANUVIA in
combination with these medications the risks of hypoglycemia, its symptoms and
treatment, and conditions that predispose to its development [see Warnings and Precautions (5.4)].
Approved Drug Label (PDF)
6
Adverse Reactions
Clinical Trials Experience
Additions and/or revisions underlined:
In an additional, 30-week placebo-controlled, study of patients
with type 2 diabetes
inadequately controlled with metformin comparing the
maintenance of sitagliptin 100 mg versus withdrawal of sitagliptin when initiating basal insulin
therapy, the event rate and incidence
of documented symptomatic hypoglycemia (blood glucose measurement ?70
mg/dL) did not differ between the sitagliptin and placebo
groups.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
Additions and/or revisions underlined:
Pancreatitis
Inform
patients that acute pancreatitis has been reported during postmarketing use of JANUVIA. 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. Instruct patients to promptly discontinue JANUVIA and contact
their physician if persistent severe abdominal pain occurs.
Heart Failure
Inform patients of the signs and symptoms of heart failure. Before initiating JANUVIA, ask
patients about
a history of heart
failure or other risk factors
for heart failure
including moderate to severe renal impairment. Instruct patients to contact their health care 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.
Hypoglycemia
Inform patients that the incidence of hypoglycemia is increased when JANUVIA
is added to a sulfonylurea or insulin
and that a lower dose of the sulfonylurea or insulin
may be required
to reduce the risk of
hypoglycemia.
New headings for
existing text:
Severe and Disabling Arthralgia
Bullous Pemphigoid
Approved Drug Label (PDF)
5
Warnings and Precautions
5.3 Assessment of Renal Function
Impairment replaces insufficiency
throughout this subsection.
Additions
and/or revisions underlined:
Caution should be used to ensure that the
correct dose of JANUVIA is prescribed for patients with moderate (eGFR greater
than or equal to 30 mL/min/1.73 m2 to less than 45 mL/min/1.73 m2)
or severe (eGFR less than 30 mL/min/1.73 m2) renal impairment.
6
Adverse Reactions
6.2 Postmarketing Experience
Addition
of the following to adverse reactions:
mouth ulceration; stomatitis.
7
Drug Interactions
7.2 Insulin Secretagogues or Insulin
Newly
added subsection:
Coadministration of JANUVIA 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
8.1 Pregnancy
PLLR
conversion; additions underlined:
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to JANUVIA during pregnancy. Health care providers are encouraged to report …
Risk Summary
The limited available data with JANUVIA in pregnant women are not sufficient to inform a drug- associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy. No adverse developmental effects were observed when sitagliptin was administered to pregnant rats and rabbits
during organogenesis at oral doses up to 30-times and 20-times, respectively, the 100 mg clinical dose, based on AUC.
The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a Hemoglobin A1c greater than 7% and has been reported to be as high as 20-25% in women with a Hemoglobin A1c greater than 10%. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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, spontaneous abortions, preterm delivery, still birth, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.
Data
Animal Data
In embryo-fetal
development studies, sitagliptin administered to pregnant rats and rabbits
during organogenesis (gestation
day 6 to 20) did not adversely affect developmental outcomes at oral
doses up to 250 mg/kg (30-times the 100 mg clinical dose) and 125
mg/kg (20-times the 100 mg clinical dose), respectively, based on AUC.
Higher doses in rats associated with maternal toxicity increased the incidence
of rib malformations in offspring at 1000 mg/kg, or approximately 100-times
the clinical dose, based on AUC. Placental transfer of sitagliptin was observed
in pregnant rats and rabbits.
Sitagliptin
administered to female rats from gestation day 6 to lactation day 21 caused no
functional or behavioral toxicity in offspring of rats at doses up to 1000
mg/kg.
8.2 Lactation
PLLR conversion;
additions underlined:
Risk Summary
There is no
information regarding the presence of JANUVIA in human milk, the effects on the
breastfed infant, or the effects on milk production. Sitagliptin is present in
rat milk and therefore possibly
present in human
milk. The developmental and health benefits of breastfeeding should be
considered along with the mother’s clinical need for JANUVIA and any potential
adverse effects on the breastfed infant from JANUVIA or from the underlying
maternal condition.
Data
Sitagliptin is secreted in the milk of lactating rats
at a milk to plasma ratio of 4:1.
8.5 Geriatric Use
Additions
and/or revisions underlined:
Because sitagliptin is substantially
excreted by the kidney, and because aging can be associated with reduced
renal function, renal function should be assessed more frequently in elderly
patients.
8.6 Renal Impairment
Newly
added subsection:
Sitagliptin is excreted by the kidney, and
sitagliptin exposure is increased in patients with renal impairment. Lower
dosages are recommended in patients with eGFR less than 45 mL/min/1.73 m2
(moderate and severe renal impairment, as well as in ESRD patients requiring
dialysis).
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Heart Failure
(Newly added subsection)
An association
between dipeptidyl peptidase-4 (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 JANUVIA 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 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 JANUVIA.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
17.1 Instructions
(Additions and/or revisions are underlined)
Patients should
be informed of the signs and symptoms of heart failure. Before initiating
JANUVIA, patients should be asked about a history of heart failure or other
risk factors for heart failure including moderate to severe renal impairment.
Patients should be instructed to contact their health care 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 JANUVIA?
Serious side effects can happen in people
taking JANUVIA, including:
- Heart failure. Heart failure means your heart does
not pump blood well enough. Before
you start taking JANUVIA, 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)
5
Warnings and Precautions
5.6 Bullous Pemphigoid
(Newly
added subsection)
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 JANUVIA. If bullous pemphigoid is suspected, JANUVIA should be
discontinued and referral to a dermatologist should be considered for diagnosis
and appropriate treatment.
6
Adverse Reactions
6.2 Postmarketing Experience
(Additions
and/or revisions are underlined)
…Hypersensitivity
reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous
vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome;
hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal
hemorrhagic and necrotizing pancreatitis; worsening renal function, including
acute renal failure (sometimes requiring dialysis); severe and disabling
arthralgia; bullous pemphigoid…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions
and/or revisions are underlined)
Advise
the patient to read the FDA-approved patient labeling (Medication Guide).
17.1 Instructions
(Additions and/or revisions are underlined)
Inform
patients that bullous pemphigoid may occur with this class of drugs. Instruct
patients to seek medical advice if blisters or erosions occur.
Medication Guide
(Additions
and/or revisions are underlined)
What
are the possible side effects of JANUVIA? Serious side effects have happened in
people taking JANUVIA.
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