Onglyza
Generic Name: saxagliptin
Dosage Form: tablet, film coated
Indications and Usage for Onglyza
Monotherapy and Combination Therapy
Onglyza
is indicated as an adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes mellitus [see Clinical Studies (14)].
Limitation of Use
Onglyza
is not indicated for the treatment of type 1 diabetes mellitus or diabetic
ketoacidosis, as it would not be effective in these settings.
Onglyza Dosage and Administration
Recommended Dosage
The
recommended dosage of Onglyza is 2.5 mg or 5 mg once daily taken regardless of
meals. Onglyza tablets must not be split or cut.
Dosage in Patients with Renal Impairment
No dosage adjustment for Onglyza is recommended for patients
with eGFR ≥45mL/min/1.73 m2.
The dosage of Onglyza is 2.5 mg once daily (regardless of meals)
for patients with eGFR <45mL/min1.73 m2 (which includes a subset of moderate or severe renal
impairment, or with end-stage renal disease (ESRD) requiring hemodialysis) [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. Onglyza should be administered following hemodialysis. Onglyza
has not been studied in patients undergoing peritoneal dialysis.
Because the dosage of Onglyza should be limited to 2.5 mg based
upon renal function, assessment of renal function is recommended prior to
initiation of Onglyza and periodically thereafter.
Dosage Adjustment with Concomitant Use of Strong
CYP3A4/5 Inhibitors
The
dosage of Onglyza is 2.5 mg once daily when coadministered with strong
cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir,
clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir,
saquinavir, and telithromycin) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Concomitant Use with an Insulin Secretagogue (e.g.,
Sulfonylurea) or with Insulin
When
Onglyza is used in combination with an insulin secretagogue (e.g.,
sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or
insulin may be required to minimize the risk of hypoglycemia [see
Warnings and Precautions (5.3)].
Dosage Forms and Strengths
•
Onglyza
(saxagliptin) 5 mg tablets are pink, biconvex, round, film-coated tablets with
“5” printed on one side and “4215” printed on the reverse side, in blue ink.
•
Onglyza
(saxagliptin) 2.5 mg tablets are pale yellow to light yellow, biconvex, round,
film-coated tablets with “2.5” printed on one side and “4214” printed on the
reverse side, in blue ink.
Contraindications
Onglyza is contraindicated in patients with a history of a
serious hypersensitivity reaction to Onglyza, such as anaphylaxis, angioedema,
or exfoliative skin conditions [see Warnings and Precautions (5.4) and Adverse Reactions (6.2)].
Warnings and Precautions
Pancreatitis
There have been postmarketing
reports of acute pancreatitis in patients taking Onglyza. 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 Onglyza compared to 9 of 8173 (0.1%) receiving
placebo. Preexisting risk factors for pancreatitis were identified in 88%
(15/17) of those patients receiving Onglyza and in 100% (9/9) of those patients
receiving placebo.
After initiation of Onglyza, observe patients for
signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly
discontinue Onglyza 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 Onglyza.
Heart Failure
In a cardiovascular
outcomes trial enrolling participants with established ASCVD or multiple risk
factors for ASCVD (SAVOR trial), more patients randomized to Onglyza (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 Onglyza 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 Onglyza prior to
initiating treatment in patients at a higher risk for 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 Onglyza.
Hypoglycemia with Concomitant Use of Sulfonylurea or
Insulin
When Onglyza was used in combination with a sulfonylurea or with
insulin, medications known to cause hypoglycemia, the incidence of confirmed
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 the insulin secretagogue or
insulin may be required to minimize the risk of hypoglycemia when used in
combination with Onglyza [see Dosage and Administration (2.4)].
Hypersensitivity Reactions
There have been postmarketing reports of serious
hypersensitivity reactions in patients treated with Onglyza. These reactions
include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of
these reactions occurred within the first 3 months after initiation of
treatment with Onglyza, with some reports occurring after the first dose. If a
serious hypersensitivity reaction is suspected, discontinue Onglyza, assess for
other potential causes for the event, and institute alternative treatment for
diabetes [see Adverse Reactions (6.2)].
Use caution in a patient with a history of angioedema to another
dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such
patients will be predisposed to angioedema with Onglyza.
Severe and Disabling Arthralgia
There have been postmarketing reports of severe and disabling
arthralgia in patients taking DPP4 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 when restarting the same drug
or a different DPP4 inhibitor. Consider DPP4 inhibitors as a possible cause for
severe joint pain and discontinue drug if appropriate.
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 Onglyza. If bullous pemphigoid is suspected, Onglyza should be
discontinued and referral to a dermatologist should be considered for diagnosis
and appropriate treatment.
Macrovascular Outcomes
There have been no
clinical studies establishing conclusive evidence of macrovascular risk
reduction with Onglyza.
Adverse Reactions
The following serious adverse reactions are described below or
elsewhere in the prescribing information:
• Pancreatitis [see Warnings and Precautions (5.1)]
• Heart Failure [see Warnings and Precautions (5.2)]
• Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see Warnings and Precautions (5.3)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
• Severe and disabling arthralgia [see Warnings and Precautions (5.5)]
• Bullous pemphigoid [see Warnings and Precautions (5.6)]
Clinical Trials Experience
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of a drug
cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
Adverse Reactions in Efficacy Trials
The data in Table 1 are derived from a pool of 5
placebo-controlled clinical trials [see Clinical Studies (14)]. These data shown in the table reflect exposure of 882
patients to Onglyza and a mean duration of exposure to Onglyza of 21 weeks. The
mean age of these patients was 55 years, 1.4 % were 75 years or older and 48.4%
were male. The population was 67.5% White, 4.6% Black or African American,
17.4% Asian, Other 10.5% and 9.8% were of Hispanic or Latino ethnicity. At
baseline the population had diabetes for an average of 5.2 years and a mean
HbA1c of 8.2%. Baseline estimated renal function was normal or mildly impaired
(eGFR≥60mL/min/1.73m2) in 91% of these patients.
Table 1 shows common adverse reactions, excluding hypoglycemia,
associated with the use of Onglyza. These adverse reactions occurred more
commonly on Onglyza than on placebo and occurred in at least 5% of patients
treated with Onglyza.
Table 1: Adverse Reactions in Placebo-Controlled Trials* Reported in ≥5% of Patients
Treated with Onglyza 5 mg and More Commonly than in Patients Treated with
Placebo
|
|
|
% of Patients
|
|
|
Onglyza 5 mg
N=882
|
Placebo
N=799
|
|
*
The 5 placebo-controlled trials include two
monotherapy trials and one add-on combination therapy trial with each of the
following: metformin, thiazolidinedione, or glyburide. Table shows 24-week
data regardless of glycemic rescue.
|
|
Upper respiratory tract infection
|
7.7
|
7.6
|
|
Urinary tract infection
|
6.8
|
6.1
|
|
Headache
|
6.5
|
5.9
|
In patients treated with Onglyza 2.5 mg, headache (6.5%) was the
only adverse reaction reported at a rate ≥5% and more commonly than in patients
treated with placebo.
In the add-on to TZD trial, the incidence of peripheral edema
was higher for Onglyza 5 mg versus placebo (8.1% and 4.3%, respectively). The
incidence of peripheral edema for Onglyza 2.5 mg was 3.1%. None of the reported
adverse reactions of peripheral edema resulted in study drug discontinuation.
Rates of peripheral edema for Onglyza 2.5 mg and Onglyza 5 mg versus placebo
were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1% versus 2.2%
given as add-on therapy to metformin, and 2.4% and 1.2% versus 2.2% given as add-on
therapy to glyburide.
The incidence rate of fractures was 1.0 and 0.6 per 100
patient-years, respectively, for Onglyza (pooled analysis of 2.5 mg, 5 mg, and
10 mg) and placebo. The 10 mg dosage is not an approved dosage. The incidence
rate of fracture events in patients who received Onglyza did not increase over
time. Causality has not been established and nonclinical studies have not
demonstrated adverse effects of Onglyza on bone.
An event of thrombocytopenia, consistent with a diagnosis of
idiopathic thrombocytopenic purpura, was observed in the clinical program. The
relationship of this event to Onglyza is not known.
Discontinuation of therapy due to adverse reactions occurred in
2.2%, 3.3%, and 1.8% of subjects receiving Onglyza 2.5 mg, Onglyza 5 mg, and
placebo, respectively. The most common adverse reactions (reported in at least
2 subjects treated with Onglyza 2.5 mg or at least 2 subjects treated with
Onglyza 5 mg) associated with premature discontinuation of therapy included
lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3% versus
0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine
phosphokinase increased (0.1% and 0.2% versus 0%).
Adverse Reactions with Concomitant
Use with Insulin
In the add-on to insulin trial [see Clinical Studies (14.1)], the incidence of adverse events, including serious adverse
events and discontinuations due to adverse events, was similar between Onglyza
and placebo, except for confirmed hypoglycemia [see Adverse Reactions (6.1)].
Hypoglycemia
Adverse reactions of hypoglycemia were based on all reports of
hypoglycemia. A concurrent glucose measurement was not required or was normal
in some patients. Therefore, it is not possible to conclusively determine that
all these reports reflect true hypoglycemia.
In the add-on to glyburide study, the overall incidence of
reported hypoglycemia was higher for Onglyza 2.5 mg and Onglyza 5 mg (13.3% and
14.6%) versus placebo (10.1%). The incidence of confirmed hypoglycemia in this
study, defined as symptoms of hypoglycemia accompanied by a fingerstick glucose
value of ≤50 mg/dL, was 2.4% and 0.8% for Onglyza 2.5 mg and Onglyza 5 mg and
0.7% for placebo [see Warnings and Precautions (5.3)]. The incidence of reported hypoglycemia for Onglyza
2.5 mg and Onglyza 5 mg versus placebo given as monotherapy was 4% and 5.6%
versus 4.1%, respectively, 7.8% and 5.8% versus 5% given as add-on therapy to
metformin, and 4.1% and 2.7% versus 3.8% given as add-on therapy to TZD. The
incidence of reported hypoglycemia was 3.4% in treatment-naive patients given
Onglyza 5 mg plus metformin and 4% in patients given metformin alone.
In the active-controlled trial comparing add-on therapy with
Onglyza 5 mg to glipizide in patients inadequately controlled on metformin
alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients)
with Onglyza 5 mg versus 36.3% (750 events in 156 patients) with
glipizide. Confirmed symptomatic hypoglycemia (accompanying fingerstick blood
glucose ≤50 mg/dL) was reported in none of the Onglyza-treated patients and in
35 glipizide-treated patients (8.1%) (p<0.0001).
In the add-on to insulin trial, the overall incidence of
reported hypoglycemia was 18.4% for Onglyza 5 mg and 19.9% for placebo.
However, the incidence of confirmed symptomatic hypoglycemia (accompanying
fingerstick blood glucose ≤50 mg/dL) was higher with Onglyza 5 mg (5.3%) versus
placebo (3.3%).
In the add-on to metformin plus sulfonylurea trial, the overall
incidence of reported hypoglycemia was 10.1% for Onglyza 5 mg and 6.3% for
placebo. Confirmed hypoglycemia was reported in 1.6% of the Onglyza-treated
patients and in none of the placebo-treated patients [see Warnings and Precautions (5.3)].
Hypersensitivity Reactions
Hypersensitivity-related events, such as urticaria and facial
edema in the 5-study pooled analysis up to Week 24 were reported in 1.5%, 1.5%,
and 0.4% of patients who received Onglyza 2.5 mg, Onglyza 5 mg, and placebo,
respectively. None of these events in patients who received Onglyza required
hospitalization or were reported as life-threatening by the investigators. One
Onglyza-treated patient in this pooled analysis discontinued due to generalized
urticaria and facial edema.
Renal Impairment
In the SAVOR trial, adverse reactions related to renal
impairment, including laboratory changes (i.e., doubling of serum creatinine
compared with baseline and serum creatinine >6 mg/dL), were reported in 5.8%
(483/8280) of Onglyza-treated subjects and 5.1% (422/8212) of placebo-treated
subjects. The most frequently reported adverse reactions included renal
impairment (2.1% vs. 1.9%), acute renal failure (1.4% vs. 1.2%), and renal
failure (0.8% vs. 0.9%), in the Onglyza versus placebo groups, respectively.
From baseline to the end of treatment, there was a mean decrease in eGFR of 2.5
mL/min/1.73m2 for Onglyza-treated patients and a mean decrease of 2.4
mL/min/1.73m2 for placebo-treated patients. More subjects randomized to
Onglyza (421/5227, 8.1%) compared to subjects randomized to placebo (344/5073,
6.8%) had downward shifts in eGFR from >50 mL/min/1.73m2 (i.e.,
normal or mild renal impairment) to ≤50 mL/min/1.73m2 (i.e.,
moderate or severe renal impairment). The proportions of subjects with renal
adverse reactions increased with worsening baseline renal function and
increased age, regardless of treatment assignment.
Infections
In the unblinded, controlled, clinical trial database for
Onglyza to date, there have been 6 (0.12%) reports of tuberculosis among the
4959 Onglyza-treated patients (1.1 per 1000 patient-years) compared to no
reports of tuberculosis among the 2868 comparator-treated patients. Two of
these six cases were confirmed with laboratory testing. The remaining cases had
limited information or had presumptive diagnoses of tuberculosis. None of the
six cases occurred in theUnited Statesor inWestern Europe. One case occurred inCanadain a patient originally fromIndonesiawho had recently visitedIndonesia. The
duration of treatment with Onglyza until report of tuberculosis ranged from 144
to 929 days. Post-treatment lymphocyte counts were consistently within the
reference range for four cases. One patient had lymphopenia prior to initiation
of Onglyza that remained stable throughout Onglyza treatment. The final patient
had an isolated lymphocyte count below normal approximately four months prior
to the report of tuberculosis. There have been no spontaneous reports of
tuberculosis associated with Onglyza use. Causality has not been estimated and
there are too few cases to date to determine whether tuberculosis is related to
Onglyza use.
There has been one case of a potential opportunistic infection
in the unblinded, controlled clinical trial database to date in an
Onglyza-treated patient who developed suspected foodborne fatal salmonella
sepsis after approximately 600 days of Onglyza therapy. There have been no
spontaneous reports of opportunistic infections associated with Onglyza use.
Vital Signs
No clinically meaningful changes in vital signs have been
observed in patients treated with Onglyza.
Laboratory Tests
Absolute Lymphocyte Counts
There was a dose-related mean decrease in absolute lymphocyte
count observed with Onglyza. From a baseline mean absolute lymphocyte count of
approximately 2200 cells/microL, mean decreases of approximately 100 and 120
cells/microL with Onglyza 5 mg and 10 mg, respectively, relative to placebo
were observed at 24 weeks in a pooled analysis of five placebo-controlled
clinical studies. Similar effects were observed when Onglyza 5 mg was given in
initial combination with metformin compared to metformin alone. There was no
difference observed for Onglyza 2.5 mg relative to placebo. The proportion of
patients who were reported to have a lymphocyte count ≤750 cells/microL was
0.5%, 1.5%, 1.4%, and 0.4% in the Onglyza 2.5 mg, 5 mg, 10 mg, and placebo
groups, respectively. In most patients, recurrence was not observed with
repeated exposure to Onglyza although some patients had recurrent decreases
upon rechallenge that led to discontinuation of Onglyza. The decreases in
lymphocyte count were not associated with clinically relevant adverse
reactions. The 10 mg dosage is not an approved dosage.
In the SAVOR trial mean decreases of approximately 84
cells/microL with Onglyza relative to placebo was observed. The proportion of
patients who experienced a decrease in lymphocyte counts to a count of ≤750
cells/microL was 1.6% (136/8280) and 1.0% (78/8212) on Onglyza and placebo
respectively.
The clinical significance of this decrease in lymphocyte count
relative to placebo is not known. When clinically indicated, such as in
settings of unusual or prolonged infection, lymphocyte count should be
measured. The effect of Onglyza on lymphocyte counts in patients with
lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.
Postmarketing Experience
Additional adverse reactions have been identified during
post-approval use of Onglyza. 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.
•
Hypersensitivity
reactions including anaphylaxis, angioedema, and exfoliative skin conditions [see Contraindications (4) and Warnings
and Precautions (5.4)].
•
Pancreatitis
[see Warnings
and Precautions (5.1)].
•
Severe
and disabling arthralgia [see Warnings and Precautions (5.5)].
•
Bullous
pemphigoid [seeWarnings and Precautions (5.6)].
Drug Interactions
Strong Inhibitors of CYP3A4/5 Enzymes
Ketoconazole significantly increased saxagliptin exposure.
Similar significant increases in plasma concentrations of saxagliptin are
anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir,
clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir,
saquinavir, and telithromycin). The dose of Onglyza should be limited to 2.5 mg
when coadministered with a strong CYP3A4/5 inhibitor [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
Limited data with Onglyza in pregnant women are not sufficient
to determine a drug-associated risk for major birth defects or miscarriages.
There are risks to the mother and fetus associated with poorly controlled
diabetes in pregnancy [see Clinical Considerations].
No adverse developmental effects independent of maternal
toxicity were observed when saxagliptin was administered to pregnant rats and
rabbits during the period of organogenesis and in pregnant and lactating rats
during the pre- and postnatal period [see Data].
The estimated background risk of major birth defects in 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 theU.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, preeclampsia, spontaneous abortions, preterm
delivery, still birth and delivery complications. Poorly controlled diabetes
increases the fetal risk for major birth defects, stillbirth, and macrosomia related
morbidity.
Animal Data
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 pregnant rats.
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.
Lactation
Risk Summary
There is
no information regarding the presence of Onglyza in human milk, the effects on
the breastfed infant, or the effects on milk production.
Saxagliptin
is present in the milk of lactating rats [see Data].
The developmental and health benefits of breastfeeding should be considered
along with the mother’s clinical need for Onglyza and any potential adverse
effects on the breastfed infant from Onglyza or from the underlying maternal
condition.
Data
Saxagliptin
is secreted in the milk of lactating rats at approximately a 1:1 ratio with
plasma drug concentrations.
Pediatric Use
Safety
and effectiveness of Onglyza in pediatric patients under 18 years of age have
not been established. Additionally, studies characterizing the pharmacokinetics
of Onglyza in pediatric patients have not been performed.
Geriatric Use
In the
seven, double-blind, controlled clinical safety and efficacy trials of Onglyza,
a total of 4751 (42.0%) of the 11301 patients randomized to Onglyza 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.
Saxagliptin
and its active metabolite are eliminated in part by the kidney. Because elderly
patients are more likely to have decreased renal function, care should be taken
in dose selection in the elderly based on renal function [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Renal Impairment
In a
12-week randomized placebo-controlled trial, Onglyza 2.5 mg was administered to
85 subjects with moderate (n=48) or severe (n=18) renal impairment or end-stage
renal disease (ESRD) (n=19) [see Clinical Studies (14)]. The incidence of adverse events, including serious adverse
events and discontinuations due to adverse events, was similar between Onglyza
and placebo. The overall incidence of reported hypoglycemia was 20% among subjects
treated with Onglyza 2.5 mg and 22% among subjects treated with placebo. Four
Onglyza-treated subjects (4.7%) and three placebo-treated subjects (3.5%)
reported at least one episode of confirmed symptomatic hypoglycemia
(accompanying fingerstick glucose ≤50 mg/dL).
Overdosage
In a
controlled clinical trial, once-daily, orally-administered Onglyza in healthy
subjects at doses up to 400 mg daily for 2 weeks (80 times the MRHD) had no
dose-related clinical adverse reactions and no clinically meaningful effect on
QTc interval or heart rate.
In the
event of an overdose, appropriate supportive treatment should be initiated as
dictated by the patient’s clinical status. Saxagliptin and its active
metabolite are removed by hemodialysis (23% of dose over 4 hours).
Onglyza Description
Saxagliptin
is an orally-active inhibitor of the DPP4 enzyme.
Saxagliptin
monohydrate is described chemically as (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile,
monohydrate or (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile
hydrate. The empirical formula is C18H25N3O2•H2O and the molecular weight is 333.43. The structural
formula is:
Saxagliptin
monohydrate is a white to light yellow or light brown, non-hygroscopic,
crystalline powder. It is sparingly soluble in water at 24°C ± 3°C, slightly
soluble in ethyl acetate, and soluble in methanol, ethanol, isopropyl alcohol,
acetonitrile, acetone, and polyethylene glycol 400 (PEG 400).
Each
film-coated tablet of Onglyza for oral use contains either 2.79 mg saxagliptin
hydrochloride (anhydrous) equivalent to 2.5 mg saxagliptin or 5.58 mg
saxagliptin hydrochloride (anhydrous) equivalent to 5 mg saxagliptin and the
following inactive ingredients: lactose monohydrate, microcrystalline
cellulose, croscarmellose sodium, and magnesium stearate. In addition, the film
coating contains the following inactive ingredients: polyvinyl alcohol,
polyethylene glycol, titanium dioxide, talc, and iron oxides.
Onglyza - Clinical Pharmacology
Mechanism of Action
Increased
concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1)
and glucose-dependent insulinotropic polypeptide (GIP) are released into the
bloodstream from the small intestine in response to meals. These hormones cause
insulin release from the pancreatic beta cells in a glucose-dependent manner
but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers
glucagon secretion from pancreatic alpha cells, reducing hepatic glucose
production. In patients with type 2 diabetes, concentrations of GLP-1 are
reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a
competitive DPP4 inhibitor that slows the inactivation of the incretin
hormones, thereby increasing their bloodstream concentrations and reducing
fasting and postprandial glucose concentrations in a glucose-dependent manner
in patients with type 2 diabetes mellitus.
Pharmacodynamics
In
patients with type 2 diabetes mellitus, administration of Onglyza inhibits DPP4
enzyme activity for a 24-hour period. After an oral glucose load or a meal,
this DPP4 inhibition resulted in a 2- to 3-fold increase in circulating levels
of active GLP-1 and GIP, decreased glucagon concentrations, and increased
glucose-dependent insulin secretion from pancreatic beta cells. The rise in
insulin and decrease in glucagon were associated with lower fasting glucose
concentrations and reduced glucose excursion following an oral glucose load or
a meal.
Cardiac Electrophysiology
In a
randomized, double-blind, placebo-controlled, 4-way crossover, active
comparator study using moxifloxacin in 40 healthy subjects, Onglyza was not
associated with clinically meaningful prolongation of the QTc interval or heart
rate at daily doses up to 40 mg (8 times the MRHD).
Pharmacokinetics
The
pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy
saxagliptin were similar in healthy subjects and in patients with type 2
diabetes mellitus. The Cmax and
AUC values of saxagliptin and its active metabolite increased proportionally in
the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin
to healthy subjects, the mean plasma AUC values for saxagliptin and its active
metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding
plasma Cmaxvalues were 24 ng/mL and 47 ng/mL, respectively. The
average variability (%CV) for AUC and Cmax for
both saxagliptin and its active metabolite was less than 25%.
No
appreciable accumulation of either saxagliptin or its active metabolite was
observed with repeated once-daily dosing at any dose level. No dose- and
time-dependence were observed in the clearance of saxagliptin and its active
metabolite over 14 days of once-daily dosing with saxagliptin at doses
ranging from 2.5 to 400 mg.
Absorption
The
median time to maximum concentration (Tmax)
following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours
for its active metabolite. Administration with a high-fat meal resulted in an
increase in Tmax of saxagliptin by approximately 20 minutes as
compared to fasted conditions. There was a 27% increase in the AUC of
saxagliptin when given with a meal as compared to fasted conditions. Onglyza
may be administered with or without food.
Distribution
The in
vitro protein binding of saxagliptin and its active
metabolite in human serum is negligible. Therefore, changes in blood protein
levels in various disease states (e.g., renal or hepatic impairment) are not
expected to alter the disposition of saxagliptin.
Metabolism
The
metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5
(CYP3A4/5). The major metabolite of saxagliptin is also a DPP4 inhibitor, which
is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and
inducers will alter the pharmacokinetics of saxagliptin and its active
metabolite [see Drug Interactions (7.1)].
Excretion
Saxagliptin
is eliminated by both renal and hepatic pathways. Following a single 50 mg dose
of 14C-saxagliptin, 24%, 36%, and 75% of the dose was
excreted in the urine as saxagliptin, its active metabolite, and total
radioactivity, respectively. The average renal clearance of saxagliptin (~230
mL/min) was greater than the average estimated glomerular filtration rate (~120
mL/min), suggesting some active renal excretion. A total of 22% of the
administered radioactivity was recovered in feces representing the fraction of
the saxagliptin dose excreted in bile and/or unabsorbed drug from the
gastrointestinal tract. Following a single oral dose of Onglyza 5 mg to healthy
subjects, the mean plasma terminal half-life (t1/2)
for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.
Specific Populations
Renal Impairment
A
single-dose, open-label study was conducted to evaluate the pharmacokinetics of
saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal
impairment compared to subjects with normal renal function. The 10 mg dosage is
not an approved dosage.
The
degree of renal impairment did not affect Cmax of
saxagliptin or its metabolite. In subjects with moderate renal impairment with
(eGFR 30 to less than 45 mL/min/1.73m2), severe
renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2)
and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active
metabolite were >2 fold higher than AUC values in subjects with normal renal
function.
Hepatic Impairment
In
subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean Cmax and AUC of saxagliptin were up to 8% and 77%
higher, respectively, compared to healthy matched controls following
administration of a single 10 mg dose of saxagliptin. The 10 mg dosage is not
an approved dosage. The corresponding Cmax and
AUC of the active metabolite were up to 59% and 33% lower, respectively,
compared to healthy matched controls. These differences are not considered to
be clinically meaningful.
Body Mass Index
No dosage
adjustment is recommended based on body mass index (BMI) which was not
identified as a significant covariate on the apparent clearance of saxagliptin
or its active metabolite in the population pharmacokinetic analysis.
Gender
No dosage
adjustment is recommended based on gender. There were no differences observed
in saxagliptin pharmacokinetics between males and females. Compared to males,
females had approximately 25% higher exposure values for the active metabolite
than males, but this difference is unlikely to be of clinical relevance. Gender
was not identified as a significant covariate on the apparent clearance of
saxagliptin and its active metabolite in the population pharmacokinetic
analysis.
Geriatric
No dosage
adjustment is recommended based on age alone. Elderly subjects (65-80 years)
had 23% and 59% higher geometric mean Cmax and
geometric mean AUC values, respectively, for saxagliptin than young subjects
(18-40 years). Differences in active metabolite pharmacokinetics between
elderly and young subjects generally reflected the differences observed in
saxagliptin pharmacokinetics. The difference between the pharmacokinetics of
saxagliptin and the active metabolite in young and elderly subjects is likely
due to multiple factors including declining renal function and metabolic
capacity with increasing age. Age was not identified as a significant covariate
on the apparent clearance of saxagliptin and its active metabolite in the
population pharmacokinetic analysis.
Race and Ethnicity
No dosage
adjustment is recommended based on race. The population pharmacokinetic
analysis compared the pharmacokinetics of saxagliptin and its active metabolite
in 309 Caucasian subjects with 105 non-Caucasian subjects (consisting of six
racial groups). No significant difference in the pharmacokinetics of
saxagliptin and its active metabolite were detected between these two
populations.
Drug Interaction Studies
In Vitro Assessment of Drug
Interactions
The
metabolism of saxagliptin is primarily mediated by CYP3A4/5.
In in
vitro studies, saxagliptin and its active metabolite did
not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2,
2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic
clearance of coadministered drugs that are metabolized by these enzymes.
Saxagliptin is a P-glycoprotein (P-gp) substrate but is not a significant
inhibitor or inducer of P-gp.
In Vivo Assessment of Drug
Interactions
Table 2: Effect of Coadministered Drugs on Systemic Exposures of
Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin
|
|
Coadministered Drug
|
Dosage of
Coadministered Drug*
|
Dosage of
Saxagliptin*
|
Geometric Mean Ratio
(ratio with/without
coadministered drug)
No Effect = 1.00
|
|
|
|
|
|
AUC†
|
Cmax
|
|
*
Single dose
unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage.
†
AUC = AUC(INF)
for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple
doses
‡
Results exclude
one subject
§
The plasma dipeptidyl peptidase-4 (DPP4) activity
inhibition over a 24-hour dose interval was not affected by rifampin
|
|
No
dosing adjustments required for the following:
|
|
Metformin
|
1000 mg
|
100 mg
|
saxagliptin
5-hydroxy saxagliptin
|
0.98
0.99
|
0.79
0.88
|
|
Glyburide
|
5 mg
|
10 mg
|
saxagliptin
5-hydroxy saxagliptin
|
0.98
ND
|
1.08
ND
|
|
Dapagliflozin
|
10 mg single
dose
|
5 mg single dose
|
saxagliptin
5-hydroxy saxagliptin
|
↓1%
↑9%
|
↓7%
↑6%
|
|
Pioglitazone‡
|
45 mg QD for 10
days
|
10 mg QD for 5
days
|
saxagliptin
5-hydroxy saxagliptin
|
1.11
ND
|
1.11
ND
|
|
Digoxin
|
0.25 mg q6h
first day followed by q12h second day followed by QD for
5 days
|
10 mg QD for 7
days
|
saxagliptin
5-hydroxy saxagliptin
|
1.05
1.06
|
0.99
1.02
|
|
Simvastatin
|
40 mg QD for 8
days
|
10 mg QD for 4
days
|
saxagliptin
5-hydroxy saxagliptin
|
1.12
1.02
|
1.21
1.08
|
|
Diltiazem
|
360 mg LA QD for
9 days
|
10 mg
|
saxagliptin
5-hydroxy saxagliptin
|
2.09
0.66
|
1.63
0.57
|
|
Rifampin§
|
600 mg QD for 6
days
|
5 mg
|
saxagliptin
5-hydroxy saxagliptin
|
0.24
1.03
|
0.47
1.39
|
|
Omeprazole
|
40 mg QD for 5
days
|
10 mg
|
saxagliptin
5-hydroxy saxagliptin
|
1.13
ND
|
0.98
ND
|
|
Aluminum hydroxide + magnesium hydroxide +
simethicone
|
aluminum
hydroxide:
2400 mg
magnesium hydroxide:
2400 mg
simethicone: 240 mg
|
10 mg
|
saxagliptin
5-hydroxy saxagliptin
|
0.97
ND
|
0.74
ND
|
|
Famotidine
|
40 mg
|
10 mg
|
saxagliptin
5-hydroxy saxagliptin
|
1.03
ND
|
1.14
ND
|
|
Limit
Onglyza dose to 2.5 mg once daily when coadministered with strong CYP3A4/5
inhibitors [see Drug Interactions (7.1)and Dosage and Administration (2.3)]:
|
|
Ketoconazole
|
200 mg BID for 9
days
|
100 mg
|
saxagliptin
5-hydroxy saxagliptin
|
2.45
0.12
|
1.62
0.05
|
|
Ketoconazole
|
200 mg BID for 7
days
|
20 mg
|
saxagliptin
5-hydroxy saxagliptin
|
3.67
ND
|
2.44
ND
|
ND=not
determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice
daily; LA=long acting
Table 3: Effect of Saxagliptin on Systemic Exposures of
Coadministered Drugs
|
|
Coadministered Drug
|
Dosage of
Coadministered Drug*
|
Dosage of
Saxagliptin*
|
Geometric Mean Ratio
(ratio with/without
saxagliptin)
No Effect = 1.00
|
|
|
|
|
|
AUC†
|
Cmax
|
|
*
Single dose
unless otherwise noted. The 10 mg and 100 mg saxagliptin doses are not
approved dosages.
†
AUC = AUC(INF)
for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple
doses
‡
Results include all subjects
|
|
No
dosing adjustments required for the following:
|
|
Metformin
|
1000 mg
|
100 mg
|
metformin
|
1.20
|
1.09
|
|
Glyburide
|
5 mg
|
10 mg
|
glyburide
|
1.06
|
1.16
|
|
Pioglitazone‡
|
45 mg QD for 10
days
|
10 mg QD for 5
days
|
pioglitazone
hydroxy-pioglitazone
|
1.08
ND
|
1.14
ND
|
|
Digoxin
|
0.25 mg q6h
first day followed by q12h second day followed by QD for
5 days
|
10 mg QD for 7
days
|
digoxin
|
1.06
|
1.09
|
|
Simvastatin
|
40 mg QD for 8
days
|
10 mg QD for 4
days
|
simvastatin
simvastatin acid
|
1.04
1.16
|
0.88
1.00
|
|
Diltiazem
|
360 mg LA QD for
9 days
|
10 mg
|
diltiazem
|
1.10
|
1.16
|
|
Ketoconazole
|
200 mg BID for 9
days
|
100 mg
|
ketoconazole
|
0.87
|
0.84
|
|
Ethinyl estradiol and Norgestimate
|
ethinyl
estradiol 0.035 mg and norgestimate 0.250 mg for 21 days
|
5 mg QD for 21
days
|
ethinyl estradiol
norelgestromin
norgestrel
|
1.07
1.10
1.13
|
0.98
1.09
1.17
|
ND=not
determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice
daily; LA=long acting
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
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.
Mutagenesis
Saxagliptin
was not mutagenic or clastogenic in a battery of genotoxicity tests (Amesbacterial
mutagenesis, human and rat lymphocyte cytogenetics, rat bone marrow
micronucleus and DNA repair assays). The active metabolite of saxagliptin was
not mutagenic in anAmesbacterial 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.
Animal Toxicology and/or Pharmacology
Saxagliptin
produced adverse skin changes in the extremities of cynomolgus monkeys (scabs
and/or ulceration of tail, digits, scrotum, and/or nose). Skin lesions were
reversible within exposure approximately 20-times the 5 mg clinical dose, but
in some cases were irreversible and necrotizing at higher exposures. Adverse
skin changes were not observed at exposures similar to (1- to 3-times) the 5 mg
clinical dose. Clinical correlates to skin lesions in monkeys have not been
observed in human clinical trials of saxagliptin.
Clinical Studies
Glycemic Efficacy Trials
Onglyza
has been studied as monotherapy and in combination with metformin, glyburide,
and thiazolidinedione (pioglitazone and rosiglitazone) therapy.
A total
of 4148 patients with type 2 diabetes mellitus were randomized in six,
double-blind, controlled clinical trials conducted to evaluate the safety and
glycemic efficacy of Onglyza. A total of 3021 patients in these trials were
treated with Onglyza. In these trials, the mean age was 54 years, and 71% of
patients were Caucasian, 16% were Asian, 4% were black, and 9% were of other
racial groups. An additional 423 patients, including 315 who received Onglyza,
participated in a placebo-controlled, dose-ranging study of 6 to 12 weeks in duration.
In these
six, double-blind trials, Onglyza was evaluated at doses of 2.5 mg and 5 mg
once daily. Three of these trials also evaluated an Onglyza dose of 10 mg
daily. The 10 mg daily dose of Onglyza did not provide greater efficacy than
the 5 mg daily dose. The 10 mg dosage is not an approved dosage. Treatment with
Onglyza 5 mg and 2.5 mg doses produced clinically relevant and statistically
significant improvements in A1C, fasting plasma glucose (FPG), and 2-hour
postprandial glucose (PPG) following a standard oral glucose tolerance test
(OGTT), compared to control. Reductions in A1C were seen across subgroups
including gender, age, race, and baseline BMI.
Onglyza
was not associated with significant changes from baseline in body weight or
fasting serum lipids compared to placebo.
Onglyza
has also been evaluated in five additional trials in patients with type 2
diabetes: an active-controlled trial comparing add-on therapy with Onglyza to
glipizide in 858 patients inadequately controlled on metformin alone, a trial
comparing Onglyza to placebo in 455 patients inadequately controlled on insulin
alone or on insulin in combination with metformin, a trial comparing Onglyza to
placebo in 257 patients inadequately controlled on metformin plus a
sulfonylurea, a trial comparing Onglyza to placebo in 315 patients inadequately
controlled on dapagliflozin and metformin, and a trial comparing Onglyza to
placebo in 170 patients with type 2 diabetes and moderate or severe renal
impairment or ESRD.
Monotherapy
A total of
766 patients with type 2 diabetes inadequately controlled on diet and exercise
(A1C ≥7% to ≤10%) participated in two 24-week, double-blind, placebo-controlled
trials evaluating the efficacy and safety of Onglyza monotherapy.
In the
first trial, following a 2-week single-blind diet, exercise, and placebo
lead-in period, 401 patients were randomized to 2.5 mg, 5 mg, or 10 mg of
Onglyza or placebo. The 10 mg dosage is not an approved dosage. Patients who
failed to meet specific glycemic goals during the study were treated with
metformin rescue therapy, added on to placebo or Onglyza. Efficacy was
evaluated at the last measurement prior to rescue therapy for patients needing
rescue. Dose titration of Onglyza was not permitted.
Treatment
with Onglyza 2.5 mg and 5 mg daily provided significant improvements in A1C,
FPG, and PPG compared to placebo (Table 4). The percentage of patients who
discontinued for lack of glycemic control or who were rescued for meeting
prespecified glycemic criteria was 16% in the Onglyza 2.5 mg treatment group,
20% in the Onglyza 5 mg treatment group, and 26% in the placebo group.
Table 4: Glycemic Parameters at Week 24 in a Placebo-Controlled
Study of Onglyza Monotherapy in Patients with Type 2 Diabetes*
|
|
Efficacy Parameter
|
Onglyza
2.5 mg
N=102
|
Onglyza
5 mg
N=106
|
Placebo
N=95
|
|
*
Intent-to-treat
population using last observation on study or last observation prior to
metformin rescue therapy for patients needing rescue.
†
Least squares
mean adjusted for baseline value.
‡
p-value
<0.0001 compared to placebo
§
p-value <0.05
compared to placebo
¶
Significance was not tested for the 2-hour PPG for
the 2.5 mg dose of Onglyza.
|
|
Hemoglobin
A1C (%)
|
N=100
|
N=103
|
N=92
|
|
Baseline (mean)
|
7.9
|
8.0
|
7.9
|
|
Change from baseline (adjusted mean†)
|
−0.4
|
−0.5
|
+0.2
|
|
Difference from placebo (adjusted mean†)
|
−0.6‡
|
−0.6‡
|
|
|
95% Confidence Interval
|
(−0.9, −0.3)
|
(−0.9, −0.4)
|
|
|
Percent of patients achieving A1C <7%
|
35% (35/100)
|
38%§ (39/103)
|
24% (22/92)
|
|
Fasting
Plasma Glucose (mg/dL)
|
N=101
|
N=105
|
N=92
|
|
Baseline (mean)
|
178
|
171
|
172
|
|
Change from baseline (adjusted mean†)
|
−15
|
−9
|
+6
|
|
Difference from placebo (adjusted mean†)
|
−21§
|
−15§
|
|
|
95% Confidence Interval
|
(−31, −10)
|
(−25, −4)
|
|
|
2-hour
Postprandial Glucose (mg/dL)
|
N=78
|
N=84
|
N=71
|
|
Baseline (mean)
|
279
|
278
|
283
|
|
Change from baseline (adjusted mean†)
|
−45
|
−43
|
−6
|
|
Difference from placebo (adjusted mean†)
|
−39¶
|
−37§
|
|
|
95% Confidence Interval
|
(−61, −16)
|
(−59, −15)
|
|
A second
24-week monotherapy trial was conducted to assess a range of dosing regimens
for Onglyza. Treatment-naive patients with inadequately controlled diabetes
(A1C ≥7% to ≤10%) underwent a 2-week, single-blind diet, exercise, and placebo
lead-in period. A total of 365 patients were randomized to 2.5 mg every
morning, 5 mg every morning, 2.5 mg with possible titration to 5 mg every
morning, or 5 mg every evening of Onglyza, or placebo. Patients who failed to
meet specific glycemic goals during the study were treated with metformin
rescue therapy added on to placebo or Onglyza; the number of patients
randomized per treatment group ranged from 71 to 74.
Treatment
with either Onglyza 5 mg every morning or 5 mg every evening provided
significant improvements in A1C versus placebo (mean placebo-corrected
reductions of −0.4% and −0.3%, respectively). Treatment with Onglyza 2.5 mg
every morning also provided significant improvement in A1C versus placebo (mean
placebo-corrected reduction of −0.4%).
Combination Therapy
Add-On Combination Therapy with
Metformin
A total
of 743 patients with type 2 diabetes participated in this 24-week, randomized,
double-blind, placebo-controlled trial to evaluate the efficacy and safety of
Onglyza in combination with metformin in patients with inadequate glycemic
control (A1C ≥7% and ≤10%) on metformin alone. To qualify for enrollment,
patients were required to be on a stable dose of metformin (1500-2550 mg daily)
for at least 8 weeks.
Patients
who met eligibility criteria were enrolled in a single-blind, 2-week, dietary
and exercise placebo lead-in period during which patients received metformin at
their pre-study dose, up to 2500 mg daily. Following the lead-in period,
eligible patients were randomized to 2.5 mg, 5 mg, or 10 mg of Onglyza or
placebo in addition to their current dose of open-label metformin. The 10 mg
dosage is not an approved dosage. Patients who failed to meet specific glycemic
goals during the study were treated with pioglitazone rescue therapy, added on
to existing study medications. Dose titrations of Onglyza and metformin were
not permitted.
Onglyza
2.5 mg and 5 mg add-on to metformin provided significant improvements in A1C,
FPG, and PPG compared with placebo add-on to metformin (Table 5). Mean changes
from baseline for A1C over time and at endpoint are shown in Figure 1. The
proportion of patients who discontinued for lack of glycemic control or who
were rescued for meeting prespecified glycemic criteria was 15% in the Onglyza
2.5 mg add-on to metformin group, 13% in the Onglyza 5 mg add-on to metformin
group, and 27% in the placebo add-on to metformin group.
Table 5: Glycemic Parameters at Week 24 in a Placebo-Controlled
Study of Onglyza as Add-On Combination Therapy with Metformin*
|
|
Efficacy Parameter
|
Onglyza 2.5 mg
+
Metformin
N=192
|
Onglyza 5 mg
+
Metformin
N=191
|
Placebo
+
Metformin
N=179
|
|
*
Intent-to-treat population
using last observation on study or last observation prior to pioglitazone
rescue therapy for patients needing rescue.
†
Least squares
mean adjusted for baseline value.
‡
p-value
<0.0001 compared to placebo + metformin
§
p-value <0.05 compared to placebo + metformin
|
|
Hemoglobin
A1C (%)
|
N=186
|
N=186
|
N=175
|
|
Baseline (mean)
|
8.1
|
8.1
|
8.1
|
|
Change from baseline (adjusted mean†)
|
−0.6
|
−0.7
|
+0.1
|
|
Difference from placebo (adjusted mean†)
|
−0.7‡
|
−0.8‡
|
|
|
95% Confidence Interval
|
(−0.9, −0.5)
|
(−1.0, −0.6)
|
|
|
Percent of patients achieving A1C <7%
|
37%§ (69/186)
|
44%§ (81/186)
|
17% (29/175)
|
|
Fasting
Plasma Glucose (mg/dL)
|
N=188
|
N=187
|
N=176
|
|
Baseline (mean)
|
174
|
179
|
175
|
|
Change from baseline (adjusted mean†)
|
−14
|
−22
|
+1
|
|
Difference from placebo (adjusted mean†)
|
−16§
|
−23§
|
|
|
95% Confidence Interval
|
(−23, −9)
|
(−30, −16)
|
|
|
2-hour
Postprandial Glucose (mg/dL)
|
N=155
|
N=155
|
N=135
|
|
Baseline (mean)
|
294
|
296
|
295
|
|
Change from baseline (adjusted mean†)
|
−62
|
−58
|
−18
|
|
Difference from placebo (adjusted mean†)
|
−44§
|
−40§
|
|
|
95% Confidence Interval
|
(−60, −27)
|
(−56, −24)
|
|
Figure 1: Mean Change from Baseline in A1C in a
Placebo-Controlled Trial of Onglyza as Add-On Combination Therapy with
Metformin*
*Includes
patients with a baseline and week 24 value.
Week 24 (LOCF) includes intent-to-treat population using last observation on
study prior to pioglitazone rescue therapy for patients needing rescue. Mean
change from baseline is adjusted for baseline value.
Add-On Combination Therapy with
a Thiazolidinedione
A total of 565 patients with type 2 diabetes participated in
this 24-week, randomized, double-blind, placebo-controlled trial to evaluate
the efficacy and safety of Onglyza in combination with a thiazolidinedione
(TZD) in patients with inadequate glycemic control (A1C ≥7% to ≤10.5%) on TZD
alone. To qualify for enrollment, patients were required to be on a stable dose
of pioglitazone (30-45 mg once daily) or rosiglitazone (4 mg once daily or 8 mg
either once daily or in two divided doses of 4 mg) for at least 12 weeks.
Patients
who met eligibility criteria were enrolled in a single-blind, 2-week, dietary
and exercise placebo lead-in period during which patients received TZD at their
pre-study dose. Following the lead-in period, eligible patients were randomized
to 2.5 mg or 5 mg of Onglyza or placebo in addition to their current dose
of TZD. Patients who failed to meet specific glycemic goals during the study
were treated with metformin rescue, added on to existing study medications.
Dose titration of Onglyza or TZD was not permitted during the study. A change
in TZD regimen from rosiglitazone to pioglitazone at specified, equivalent
therapeutic doses was permitted at the investigator’s discretion if believed to
be medically appropriate.
Onglyza
2.5 mg and 5 mg add-on to TZD provided significant improvements in A1C, FPG,
and PPG compared with placebo add-on to TZD (Table 6). The proportion of
patients who discontinued for lack of glycemic control or who were rescued for
meeting prespecified glycemic criteria was 10% in the Onglyza 2.5 mg add-on to
TZD group, 6% for the Onglyza 5 mg add-on to TZD group, and 10% in the placebo
add-on to TZD group.
Table 6: Glycemic Parameters at Week 24 in a Placebo-Controlled
Study of Onglyza as Add-On Combination Therapy with a Thiazolidinedione*
|
|
Efficacy Parameter
|
Onglyza 2.5 mg
+
TZD
N=195
|
Onglyza 5 mg
+
TZD
N=186
|
Placebo
+
TZD
N=184
|
|
*
Intent-to-treat
population using last observation on study or last observation prior to
metformin rescue therapy for patients needing rescue.
†
Least squares
mean adjusted for baseline value.
‡
p-value
<0.0001 compared to placebo + TZD
§
p-value <0.05 compared to placebo + TZD
|
|
Hemoglobin
A1C (%)
|
N=192
|
N=183
|
N=180
|
|
Baseline (mean)
|
8.3
|
8.4
|
8.2
|
|
Change from baseline (adjusted mean†)
|
−0.7
|
−0.9
|
−0.3
|
|
Difference from placebo (adjusted mean†)
|
−0.4‡
|
−0.6§
|
|
|
95% Confidence Interval
|
(−0.6, −0.2)
|
(−0.8, −0.4)
|
|
|
Percent of patients achieving A1C <7%
|
42%‡ (81/192)
|
42% (77/184)
|
26% (46/180)
|
|
Fasting
Plasma Glucose (mg/dL)
|
N=193
|
N=185
|
N=181
|
|
Baseline (mean)
|
163
|
160
|
162
|
|
Change from baseline (adjusted mean†)
|
−14
|
−17
|
−3
|
|
Difference from placebo (adjusted mean†)
|
−12‡
|
−15‡
|
|
|
95% Confidence Interval
|
(−20, −3)
|
(−23, −6)
|
|
|
2-hour
Postprandial Glucose (mg/dL)
|
N=156
|
N=134
|
N=127
|
|
Baseline (mean)
|
296
|
303
|
291
|
|
Change from baseline (adjusted mean†)
|
−55
|
−65
|
−15
|
|
Difference from placebo (adjusted mean†)
|
−40‡
|
−50‡
|
|
|
95% Confidence Interval
|
(−56, −24)
|
(−66, −34)
|
|
Add-On Combination Therapy with
Glyburide
A total
of 768 patients with type 2 diabetes participated in this 24-week, randomized,
double-blind, placebo-controlled trial to evaluate the efficacy and safety of
Onglyza in combination with a sulfonylurea (SU) in patients with inadequate
glycemic control at enrollment (A1C ≥7.5% to ≤10%) on a submaximal dose of SU
alone. To qualify for enrollment, patients were required to be on a submaximal
dose of SU for 2 months or greater. In this study, Onglyza in combination with
a fixed, intermediate dose of SU was compared to titration to a higher dose of
SU.
Patients
who met eligibility criteria were enrolled in a single-blind, 4-week, dietary
and exercise lead-in period, and placed on glyburide 7.5 mg once daily.
Following the lead-in period, eligible patients with A1C ≥7% to ≤10% were
randomized to either 2.5 mg or 5 mg of Onglyza add-on to 7.5 mg glyburide or to
placebo plus a 10 mg total daily dose of glyburide. Patients who received
placebo were eligible to have glyburide up-titrated to a total daily dose of 15 mg.
Up-titration of glyburide was not permitted in patients who received Onglyza
2.5 mg or 5 mg. Glyburide could be down-titrated in any treatment group once
during the 24-week study period due to hypoglycemia as deemed necessary by the
investigator. Approximately 92% of patients in the placebo plus glyburide group
were up-titrated to a final total daily dose of 15 mg during the first 4 weeks
of the study period. Patients who failed to meet specific glycemic goals during
the study were treated with metformin rescue, added on to existing study
medication. Dose titration of Onglyza was not permitted during the study.
In
combination with glyburide, Onglyza 2.5 mg and 5 mg provided significant
improvements in A1C, FPG, and PPG compared with the placebo plus up-titrated
glyburide group (Table 7). The proportion of patients who discontinued for lack
of glycemic control or who were rescued for meeting prespecified glycemic
criteria was 18% in the Onglyza 2.5 mg add-on to glyburide group, 17% in
the Onglyza 5 mg add-on to glyburide group, and 30% in the placebo plus
up-titrated glyburide group.
Table 7: Glycemic Parameters at Week 24 in a Placebo-Controlled
Study of Onglyza as Add-On Combination Therapy with Glyburide*
|
|
Efficacy Parameter
|
Onglyza
2.5 mg
+
Glyburide
7.5 mg
N=248
|
Onglyza
5 mg
+
Glyburide
7.5 mg
N=253
|
Placebo
+
Up-Titrated Glyburide
N=267
|
|
*
Intent-to-treat
population using last observation on study or last observation prior to
metformin rescue therapy for patients needing rescue
†
Least squares
mean adjusted for baseline value
‡
p-value
<0.0001 compared to placebo + up-titrated glyburide
§
p-value <0.05 compared to placebo + up-titrated
glyburide
|
|
Hemoglobin
A1C (%)
|
N=246
|
N=250
|
N=264
|
|
Baseline (mean)
|
8.4
|
8.5
|
8.4
|
|
Change from baseline (adjusted mean†)
|
−0.5
|
−0.6
|
+0.1
|
|
Difference from up-titrated glyburide
(adjusted mean†)
|
−0.6‡
|
−0.7‡
|
|
|
95% Confidence Interval
|
(−0.8, −0.5)
|
(−0.9, −0.6)
|
|
|
Percent of patients achieving A1C <7%
|
22%§(55/246)
|
23%§ (57/250)
|
9% (24/264)
|
|
Fasting
Plasma Glucose (mg/dL)
|
N=247
|
N=252
|
N=265
|
|
Baseline (mean)
|
170
|
175
|
174
|
|
Change from baseline (adjusted mean†)
|
−7
|
−10
|
+1
|
|
Difference from up-titrated glyburide
(adjusted mean†)
|
−8§
|
−10§
|
|
|
95% Confidence Interval
|
(−14, −1)
|
(−17, −4)
|
|
|
2-hour
Postprandial Glucose (mg/dL)
|
N=195
|
N=202
|
N=206
|
|
Baseline (mean)
|
309
|
315
|
323
|
|
Change from baseline (adjusted mean†)
|
−31
|
−34
|
+8
|
|
Difference from up-titrated glyburide
(adjusted mean†)
|
−38§
|
−42§
|
|
|
95% Confidence Interval
|
(−50, −27)
|
(−53, −31)
|
|
Coadministration with Metformin
in Treatment-Naive Patients
A total
of 1306 treatment-naive patients with type 2 diabetes mellitus participated in
this 24-week, randomized, double-blind, active-controlled trial to evaluate the
efficacy and safety of Onglyza coadministered with metformin in patients with
inadequate glycemic control (A1C ≥8% to ≤12%) on diet and exercise alone.
Patients were required to be treatment-naive to be enrolled in this study.
Patients
who met eligibility criteria were enrolled in a single-blind, 1-week, dietary
and exercise placebo lead-in period. Patients were randomized to one of four
treatment arms: Onglyza 5 mg + metformin 500 mg, saxagliptin 10 mg +
metformin 500 mg, saxagliptin 10 mg + placebo, or metformin 500 mg + placebo.
The 10 mg saxagliptin dosage is not an approved dosage. Onglyza was dosed once
daily. In the 3 treatment groups using metformin, the metformin dose was
up-titrated weekly in 500 mg per day increments, as tolerated, to a
maximum of 2000 mg per day based on FPG. Patients who failed to meet specific
glycemic goals during the studies were treated with pioglitazone rescue as
add-on therapy.
Coadministration
of Onglyza 5 mg plus metformin provided significant improvements in A1C, FPG,
and PPG compared with placebo plus metformin (Table 8).
Table 8: Glycemic Parameters at Week 24 in a Placebo-Controlled
Trial of Onglyza Coadministration with Metformin in Treatment-Naive Patients*
|
|
Efficacy Parameter
|
Onglyza 5 mg
+
Metformin
N=320
|
Placebo
+
Metformin
N=328
|
|
*
Intent-to-treat
population using last observation on study or last observation prior to
pioglitazone rescue therapy for patients needing rescue.
†
Least squares
mean adjusted for baseline value.
‡
p-value
<0.0001 compared to placebo + metformin
§
p-value <0.05 compared to placebo + metformin
|
|
Hemoglobin
A1C (%)
|
N=306
|
N=313
|
|
Baseline (mean)
|
9.4
|
9.4
|
|
Change from baseline (adjusted mean†)
|
−2.5
|
−2.0
|
|
Difference from placebo + metformin
(adjusted mean†)
|
−0.5‡
|
|
|
95% Confidence Interval
|
(−0.7, −0.4)
|
|
|
Percent of patients achieving A1C <7%
|
60%§ (185/307)
|
41% (129/314)
|
|
Fasting
Plasma Glucose (mg/dL)
|
N=315
|
N=320
|
|
Baseline (mean)
|
199
|
199
|
|
Change from baseline (adjusted mean†)
|
−60
|
−47
|
|
Difference from placebo + metformin
(adjusted mean†)
|
−13§
|
|
|
95% Confidence Interval
|
(−19, −6)
|
|
|
2-hour
Postprandial Glucose (mg/dL)
|
N=146
|
N=141
|
|
Baseline (mean)
|
340
|
355
|
|
Change from baseline (adjusted mean†)
|
−138
|
−97
|
|
Difference from placebo + metformin
(adjusted mean†)
|
−41§
|
|
|
95% Confidence Interval
|
(−57, −25)
|
|
Add-On Combination Therapy with
Metformin versus Glipizide Add-On Combination Therapy with Metformin
In this
52-week, active-controlled trial, a total of 858 patients with type 2 diabetes
and inadequate glycemic control (A1C >6.5% and ≤10%) on metformin alone were
randomized to double-blind add-on therapy with Onglyza or glipizide. Patients
were required to be on a stable dose of metformin (at least 1500 mg daily) for
at least 8 weeks prior to enrollment.
Patients
who met eligibility criteria were enrolled in a single-blind, 2-week, dietary
and exercise placebo lead-in period during which patients received metformin
(1500-3000 mg based on their pre-study dose). Following the lead-in period,
eligible patients were randomized to 5 mg of Onglyza or 5 mg of glipizide in
addition to their current dose of open-label metformin. Patients in the
glipizide plus metformin group underwent blinded titration of the glipizide
dose during the first 18 weeks of the trial up to a maximum glipizide dose of
20 mg per day. Titration was based on a goal FPG ≤110 mg/dL or the highest
tolerable glipizide dose. Fifty percent (50%) of the glipizide-treated patients
were titrated to the 20-mg daily dose; 21% of the glipizide-treated patients
had a final daily glipizide dose of 5 mg or less. The mean final daily dose of
glipizide was 15 mg.
After 52
weeks of treatment, Onglyza and glipizide resulted in similar mean reductions
from baseline in A1C when added to metformin therapy (Table 9). This conclusion
may be limited to patients with baseline A1C comparable to those in the trial
(91% of patients had baseline A1C <9%).
From a
baseline mean body weight of 89 kg, there was a statistically significant mean
reduction of 1.1 kg in patients treated with Onglyza compared to a mean weight
gain of 1.1 kg in patients treated with glipizide (p<0.0001).
Table 9: Glycemic Parameters at Week 52 in an Active-Controlled
Trial of Onglyza versus Glipizide in Combination with Metformin*
|
|
Efficacy Parameter
|
Onglyza 5 mg
+
Metformin
N=428
|
Titrated Glipizide
+
Metformin
N=430
|
|
*
Intent-to-treat
population using last observation on study
†
Least squares
mean adjusted for baseline value
‡
Onglyza +
metformin is considered non-inferior to glipizide + metformin because the
upper limit of this confidence interval is less than the prespecified non-inferiority
margin of 0.35%
§
Significance not tested
|
|
Hemoglobin
A1C (%)
|
N=423
|
N=423
|
|
Baseline (mean)
|
7.7
|
7.6
|
|
Change from baseline (adjusted mean†)
|
−0.6
|
−0.7
|
|
Difference from glipizide + metformin
(adjusted mean†)
|
0.1
|
|
|
95% Confidence Interval
|
(−0.02, 0.2)‡
|
|
|
Fasting
Plasma Glucose (mg/dL)
|
N=420
|
N=420
|
|
Baseline (mean)
|
162
|
161
|
|
Change from baseline (adjusted mean†)
|
−9
|
−16
|
|
Difference from glipizide + metformin
(adjusted mean†)
|
6
|
|
|
95% Confidence Interval
|
(2, 11)§
|
|
Add-On Combination Therapy with
Insulin (with or without metformin)
A total
of 455 patients with type 2 diabetes participated in this 24-week, randomized,
double-blind, placebo-controlled trial to evaluate the efficacy and safety of
Onglyza in combination with insulin in patients with inadequate glycemic
control (A1C ≥7.5% and ≤11%) on insulin alone (N=141) or on insulin in
combination with a stable dose of metformin (N=314). Patients were required to
be on a stable dose of insulin (≥30 units to ≤150 units daily) with ≤20%
variation in total daily dose for ≥8 weeks prior to screening. Patients entered
the trial on intermediate- or long-acting (basal) insulin or premixed insulin.
Patients using short-acting insulins were excluded unless the short-acting
insulin was administered as part of a premixed insulin.
Patients
who met eligibility criteria were enrolled in a single-blind, four-week,
dietary and exercise placebo lead-in period during which patients received
insulin (and metformin if applicable) at their pretrial dose(s). Following the
lead-in period, eligible patients were randomized to add-on therapy with either
Onglyza 5 mg or placebo. Doses of the antidiabetic therapies were to remain
stable but patients were rescued and allowed to adjust the insulin regimen if
specific glycemic goals were not met or if the investigator learned that the
patient had self-increased the insulin dose by >20%. Data after rescue were
excluded from the primary efficacy analyses.
Add-on
therapy with Onglyza 5 mg provided significant improvements from baseline to
Week 24 in A1C and PPG compared with add-on placebo (Table 10). Similar mean
reductions in A1C versus placebo were observed for patients using Onglyza 5 mg
add-on to insulin alone and Onglyza 5 mg add-on to insulin in combination with
metformin (−0.4% and −0.4%, respectively). The percentage of patients who
discontinued for lack of glycemic control or who were rescued was 23% in the
Onglyza group and 32% in the placebo group.
The mean
daily insulin dose at baseline was 53 units in patients treated with Onglyza 5
mg and 55 units in patients treated with placebo. The mean change from baseline
in daily dose of insulin was 2 units for the Onglyza 5 mg group and 5 units for
the placebo group.
Table 10: Glycemic Parameters at Week 24 in a Placebo-Controlled
Trial of Onglyza as Add-On Combination Therapy with Insulin*
|
|
Efficacy Parameter
|
Onglyza 5 mg
+
Insulin
(+/− Metformin)
N=304
|
Placebo
+
Insulin
(+/− Metformin)
N=151
|
|
*
Intent-to-treat
population using last observation on study or last observation prior to
insulin rescue therapy for patients needing rescue
†
Least squares
mean adjusted for baseline value and metformin use at baseline
‡
p-value
<0.0001 compared to placebo + insulin
§
p-value <0.05 compared to placebo + insulin
|
|
Hemoglobin
A1C (%)
|
N=300
|
N=149
|
|
Baseline (mean)
|
8.7
|
8.7
|
|
Change from baseline (adjusted mean†)
|
−0.7
|
−0.3
|
|
Difference from placebo (adjusted mean†)
|
−0.4‡
|
|
|
95% Confidence Interval
|
(−0.6, −0.2)
|
|
|
2-hour
Postprandial Glucose (mg/dL)
|
N=262
|
N=129
|
|
Baseline (mean)
|
251
|
255
|
|
Change from baseline (adjusted mean†)
|
−27
|
−4
|
|
Difference from placebo (adjusted mean†)
|
−23§
|
|
|
95% Confidence Interval
|
(−37, −9)
|
|
The
change in fasting plasma glucose from baseline to Week 24 was also tested, but
was not statistically significant. The percent of patients achieving an A1C
<7% was 17% (52/300) with Onglyza in combination with insulin compared to 7%
(10/149) with placebo. Significance was not tested.
Add-On Combination Therapy with
Metformin plus Sulfonylurea
A total
of 257 patients with type 2 diabetes participated in this 24-week, randomized,
double-blind, placebo-controlled trial to evaluate the efficacy and safety of
Onglyza in combination with metformin plus a sulfonylurea in patients with
inadequate glycemic control (A1C ≥7% and ≤10%). Patients were to be on a stable
combined dose of metformin extended-release or immediate-release (at maximum
tolerated dose, with minimum dose for enrollment being 1500 mg) and a
sulfonylurea (at maximum tolerated dose, with minimum dose for enrollment being
≥50% of the maximum recommended dose) for ≥8 weeks prior to enrollment.
Patients
who met eligibility criteria were entered in a 2-week enrollment period to
allow assessment of inclusion/exclusion criteria. Following the 2-week
enrollment period, eligible patients were randomized to either double-blind
Onglyza (5 mg once daily) or double-blind matching placebo for 24 weeks. During
the 24-week double-blind treatment period, patients were to receive metformin
and a sulfonylurea at the same constant dose ascertained during enrollment.
Sulfonylurea dose could be down titrated once in the case of a major
hypoglycemic event or recurring minor hypoglycemic events. In the absence of
hypoglycemia, titration (up or down) of study medication during the treatment
period was prohibited.
Onglyza
in combination with metformin plus a sulfonylurea provided significant
improvements in A1C and PPG compared with placebo in combination with metformin
plus a sulfonylurea (Table 11). The percentage of patients who discontinued for
lack of glycemic control was 6% in the Onglyza group and 5% in the placebo
group.
Table 11: Glycemic Parameters at Week 24 in a Placebo-Controlled
Trial of Onglyza as Add-On Combination Therapy with Metformin plus
Sulfonylurea*
|
|
Efficacy Parameter
|
Onglyza 5 mg
+
Metformin plus
Sulfonylurea
N=129
|
Placebo
+
Metformin plus
Sulfonylurea
N=128
|
|
*
Intent-to-treat
population using last observation prior to discontinuation
†
Least squares
mean adjusted for baseline value
‡
p-value
<0.0001 compared to placebo + metformin plus sulfonylurea
§
p-value <0.05 compared to placebo + metformin plus
sulfonylurea
|
|
Hemoglobin
A1C (%)
|
N=127
|
N=127
|
|
Baseline (mean)
|
8.4
|
8.2
|
|
Change from baseline (adjusted mean†)
|
−0.7
|
−0.1
|
|
Difference from placebo (adjusted mean†)
|
−0.7‡
|
|
|
95% Confidence Interval
|
(−0.9, −0.5)
|
|
|
2-hour
Postprandial Glucose (mg/dL)
|
N=115
|
N=113
|
|
Baseline (mean)
|
268
|
262
|
|
Change from baseline (adjusted mean†)
|
−12
|
5
|
|
Difference from placebo (adjusted mean†)
|
−17§
|
|
|
95% Confidence Interval
|
(−32, −2)
|
|
The
change in fasting plasma glucose from baseline to Week 24 was also tested, but
was not statistically significant. The percent of patients achieving an A1C
<7% was 31% (39/127) with Onglyza in combination with metformin plus a
sulfonylurea compared to 9% (12/127) with placebo. Significance was not tested.
Add-on Combination Therapy with Metformin plus an SGLT2
Inhibitor
A total
of 315 patients with type 2 diabetes participated in this 24-week randomized,
double-blind, placebo-controlled trial to evaluate the efficacy and safety of
Onglyza added to dapagliflozin (an SGLT2 inhibitor) and metformin in patients
with a baseline of HbA1c ≥7% to ≤10.5%. The mean age of these subjects was 54.6
years, 1.6% were 75 years or older and 52.7% were female. The population was
87.9% White, 6.3% Black or African American, 4.1% Asian, and 1.6% Other race.
At baseline the population had diabetes for an average of 7.7 years and a mean
HbA1c of 7.9%. The mean eGFR at baseline was 93.4 mL/min/1.73 m2. Patients were
required to be on a stable dose of metformin (≥1500 mg per day) for at least 8
weeks prior to enrollment. Eligible subjects who completed the screening period
entered the lead in treatment period, which included open-label metformin and
10 mg dapagliflozin treatment. Following the lead-in period, eligible patients
were randomized to Onglyza 5 mg (N=153) or placebo (N =162).
The group
treated with add-on Onglyza had statistically significant greater reductions in
HbA1c from baseline versus the group treated with placebo (see Table 12).
Table 12: HbA1c Change from Baseline at
Week 24 in a Placebo-Controlled Trial of Onglyza as Add-on to Dapagliflozin
and Metformin*
|
|
*
There were 6.5% (n=10)
of randomized subjects in the saxagliptin arm and 3.1% (n=5) in the placebo
arm for whom change from baseline HbA1c data was missing at week 24. Of the
subjects who discontinued study medication early, 9.1% (1 of 11) in the
saxagliptin arm and 16.7% (1 of 6) in the placebo arm had HbA1c measured at
week 24.
†
Number of
randomized and treated patients.
‡
Analysis of
Covariance including all post-baseline data regardless of rescue or treatment
discontinuation. Model estimates calculated using multiple imputation to
model washout of the treatment effect using placebo data for all subjects
having missing week 24 data.
§
Least squares
mean adjusted for baseline value.
¶
p-value <0.0001
|
|
|
Onglyza 5 mg
(N=153)†
|
Placebo
(N=162)†
|
|
In combination with
Dapagliflozin and Metformin
|
|
Hemoglobin
A1C (%)‡
|
|
Baseline (mean)
|
8.0
|
7.9
|
|
Change from baseline (adjusted mean§)
95% Confidence Interval
|
−0.5
(−0.6, −0.4)
|
−0.2
(−0.3, −0.1)
|
|
Difference from placebo (adjusted mean)
95% Confidence Interval
|
−0.4¶
(−0.5, −0.2)
|
The known
proportion of patients achieving HbA1c <7% at Week 24 was 35.3% in the saxagliptin
treated group compared to 23.1% in the placebo treated group.
Renal Impairment
A total
of 170 patients participated in a 12-week, randomized, double-blind,
placebo-controlled trial conducted to evaluate the efficacy and safety of
Onglyza 2.5 mg once daily compared with placebo in patients with type 2
diabetes and moderate (n=90) or severe (n=41) renal impairment or ESRD (n=39).
In this trial, 98% of the patients were using background antidiabetic
medications (75% were using insulin and 31% were using oral antidiabetic
medications, mostly sulfonylureas).
After 12
weeks of treatment, Onglyza 2.5 mg provided significant improvement in A1C
compared to placebo (Table 13). In the subgroup of patients with ESRD, Onglyza
and placebo resulted in comparable reductions in A1C from baseline to Week 12.
This finding is inconclusive because the trial was not adequately powered to
show efficacy within specific subgroups of renal impairment.
After 12
weeks of treatment, the mean change in FPG was −12 mg/dL with Onglyza 2.5 mg
and −13 mg/dL with placebo. Compared to placebo, the mean change in FPG with
Onglyza was −12 mg/dL in the subgroup of patients with moderate renal
impairment, −4 mg/dL in the subgroup of patients with severe renal impairment,
and +44 mg/dL in the subgroup of patients with ESRD. These findings are
inconclusive because the trial was not adequately powered to show efficacy
within specific subgroups of renal impairment.
Table 13: A1C at Week 12 in a Placebo-Controlled Trial of Onglyza in
Patients with Renal Impairment*
|
|
Efficacy Parameter
|
Onglyza 2.5 mg
N=85
|
Placebo
N=85
|
|
*
Intent-to-treat
population using last observation on study.
†
Least squares
mean adjusted for baseline value.
‡
p-value <0.01 compared to placebo
|
|
Hemoglobin
A1C (%)
|
N=81
|
N=83
|
|
Baseline (mean)
|
8.4
|
8.1
|
|
Change from baseline (adjusted mean†)
|
−0.9
|
−0.4
|
|
Difference from placebo (adjusted mean†)
|
−0.4‡
|
|
|
95% Confidence Interval
|
(−0.7, −0.1)
|
|
Cardiovascular Safety Trial
The
cardiovascular risk of Onglyza was evaluated in SAVOR, a multicenter,
multinational, randomized, double-blind study comparing Onglyza (N=8280) to
placebo (N=8212), both administered in combination with standard of care, in
adult patients with type 2 diabetes at high risk for atherosclerotic
cardiovascular disease. Of the randomized study subjects, 97.5% completed the
trial, and the median duration of follow-up was approximately 2 years. The
trial was event-driven, and patients were followed until a sufficient number of
events were accrued.
Subjects
were at least 40 years of age, had A1C ≥6.5%, and multiple risk factors (21% of
randomized subjects) for cardiovascular disease (age ≥55 years for men and ≥60
years for women plus at least one additional risk factor of dyslipidemia, hypertension,
or current cigarette smoking) or established (79% of the randomized subjects)
cardiovascular disease defined as a history of ischemic heart disease,
peripheral vascular disease, or ischemic stroke. Overall, the use of diabetes
medications was balanced across treatment groups (metformin 69%, insulin 41%,
sulfonylureas 40%, and TZDs 6%). The use of cardiovascular disease medications
was also balanced (angiotensin-converting enzyme [ACE] inhibitors or
angiotensin receptor blockers [ARBs] 79%, statins 78%, aspirin 75%,
beta-blockers 62%, and non-aspirin antiplatelet medications 24%).
The
majority of subjects were male (67%) and Caucasian (75%) with a mean age of 65
years. Approximately 16% of the population had moderate (estimated glomerular
filtration rate [eGFR] ≥30 to ≤50 mL/min/1.73m2)
to severe (eGFR <30 mL/min/1.73m2) renal
impairment, and 13% had a prior history of heart failure. Subjects had a median
duration of type 2 diabetes mellitus of approximately 10 years, and a mean
baseline A1C level of 8.0%. Approximately 5% of subjects were treated with diet
and exercise only at baseline. Overall, the use of diabetes medications was
balanced across treatment groups (metformin 69%, insulin 41%, sulfonylureas
40%, and TZDs 6%). The use of cardiovascular disease medications was also
balanced (ACE inhibitors or ARBs 79%, statins 78%, aspirin 75%, beta-blockers
62%, and non-aspirin antiplatelet medications 24%).
The
primary analysis in SAVOR was time to first occurrence of a Major Adverse
Cardiac Event (MACE). A major adverse cardiac event in SAVOR was defined as a
cardiovascular death or a nonfatal myocardial infarction (MI) or a nonfatal
ischemic stroke. The study was designed as a non-inferiority trial with a
pre-specified risk margin of 1.3 for the hazard ratio of MACE and was also
powered for a superiority comparison if non-inferiority was demonstrated.
The
results of SAVOR, including the contribution of each component to the primary
composite endpoint, are shown in Table 14. The incidence rate of MACE was
similar in both treatment arms: 3.8 MACE per 100 patient-years on placebo vs.
3.8 MACE per 100 patient-years on Onglyza. The estimated hazard ratio of MACE
associated with Onglyza relative to placebo was 1.00 with a 95.1% confidence
interval of (0.89, 1.12). The upper bound of this confidence interval, 1.12,
excluded a risk margin larger than 1.3.
Table 14: Major Adverse Cardiovascular
Events (MACE) by Treatment Group in the SAVOR Trial
|
|
|
Onglyza
|
Placebo
|
Hazard Ratio
|
|
|
Number of Subjects
(%)
|
Rate per 100 PY
|
Number of Subjects
(%)
|
Rate per 100 PY
|
(95.1% CI)
|
|
Composite
of first event of CV death, non-fatal MI or non-fatal ischemic stroke (MACE)
|
N=8280
|
Total PY = 16308.8
|
N=8212
|
Total PY = 16156.0
|
|
|
613 (7.4)
|
3.8
|
609 (7.4)
|
3.8
|
1.00 (0.89, 1.12)
|
|
CV
death
|
245 (3.0)
|
1.5
|
234 (2.8)
|
1.4
|
|
|
Non-fatal
MI
|
233 (2.8)
|
1.4
|
260 (3.2)
|
1.6
|
|
|
Non-fatal
ischemic stroke
|
135 (1.6)
|
0.8
|
115 (1.4)
|
0.7
|
|
The
Kaplan-Meier-based cumulative event probability is presented in Figure 2 for
time to first occurrence of the primary MACE composite endpoint by treatment
arm. The curves for both Onglyza and placebo arms are close together throughout
the duration of the trial. The estimated cumulative event probability is
approximately linear for both arms, indicating that the incidence of MACE for
both arms was constant over the trial duration.
Figure 2: Cumulative Percent of Time to First MACE
Vital
status was obtained for 99% of subjects in the trial. There were 798 deaths in
the SAVOR trial. Numerically more patients (5.1%) died in the Onglyza group
than in the placebo group (4.6%). The risk of deaths from all cause (Table 15)
was not statistically different between the treatment groups (HR: 1.11; 95.1%
CI: 0.96, 1.27).
Table 15: All-cause mortality by
Treatment Group in the SAVOR Study
|
|
|
Onglyza
|
Placebo
|
Hazard Ratio
|
|
|
Number
of Subjects (%)
|
Rate
per 100 PY
|
Number
of Subjects (%)
|
Rate
per 100 PY
|
(95.1%
CI)
|
|
|
N=8280
|
PY=16645.3
|
N=8212
|
PY=16531.5
|
|
|
All-cause
mortality
|
420 (5.1)
|
2.5
|
378 (4.6)
|
2.3
|
1.11 (0.96,
1.27)
|
|
CV death
|
269 (3.2)
|
1.6
|
260 (3.2)
|
1.6
|
|
|
Non-CV death
|
151 (1.8)
|
0.9
|
118 (1.4)
|
0.7
|
|
How Supplied/Storage and Handling
How Supplied
Onglyza
(saxagliptin) tablets have markings on both sides and are available in the
strengths and packages listed in Table 16.
Table 16: Onglyza Tablet Presentations
|
|
Tablet
Strength
|
Film-Coated Tablet
Color/Shape
|
Tablet
Markings
|
Package Size
|
NDC Code
|
|
5 mg
|
pink
biconvex, round
|
“5” on one side and “4215” on the reverse, in blue ink
|
Bottles of 30
Bottles of 90
|
0310-6105-30
0310-6105-90
|
|
2.5 mg
|
pale yellow to
light yellow
biconvex, round
|
“2.5” on one side and “4214” on the reverse, in blue ink
|
Bottles of 30
Bottles of 90
|
0310-6100-30
0310-6100-90
|
Storage and Handling
Store at
20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP
Controlled Room Temperature].
Patient Counseling Information
Advise
the patient to read FDA-approved patient labeling (Medication Guide).
Medication Guide
Healthcare
providers should instruct their patients to read the Medication Guide before
starting Onglyza therapy and to reread it each time the prescription is renewed.
Patients should be instructed to inform their healthcare provider if they
develop any unusual symptom or if any existing symptom persists or worsens.
Patients
should be informed of the potential risks and benefits of Onglyza and of
alternative modes of therapy. Patients should also be informed about the
importance of adherence to dietary instructions, regular physical activity,
periodic blood glucose monitoring and A1C testing, recognition and management
of hypoglycemia and hyperglycemia, and assessment of diabetes complications.
During periods of stress such as fever, trauma, infection, or surgery,
medication requirements may change and patients should be advised to seek
medical advice promptly.
Pancreatitis
Patients
should be informed that acute pancreatitis has been reported during
postmarketing use of Onglyza. Before initiating Onglyza, patients should be
questioned about other risk factors for pancreatitis, such as a history of
pancreatitis, alcoholism, gallstones, or hypertriglyceridemia. Patients should
also be informed 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. Patients should be instructed to promptly
discontinue Onglyza and contact their healthcare provider if persistent severe
abdominal pain occurs [see Warnings and Precautions (5.1)].
Heart Failure
Patients
should be informed of the signs and symptoms of heart failure. Before
initiating Onglyza, 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 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 and Precautions (5.2)].
Hypersensitivity Reactions
Patients
should be informed that serious allergic (hypersensitivity) reactions, such as
angioedema, anaphylaxis, and exfoliative skin conditions, have been reported
during postmarketing use of Onglyza. If symptoms of these allergic reactions
(such as 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) occur, patients must stop taking Onglyza and seek
medical advice promptly.
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 (5.5)].
Bullous Pemphigoid
Inform
patients that bullous pemphigoid may occur with this class of drugs. Instruct
patients to seek medical advice if
blisters
or erosions occur [see Warnings and Precautions (5.6)].
Missed Dose
Patients should be informed that if they miss a
dose of Onglyza they should take the next dose as prescribed, unless otherwise
instructed by their healthcare provider. Patients should be instructed not to
take an extra dose the next day.
Administration Instructions
Patients should be informed that Onglyza tablets
must not be split or cut.
Laboratory Tests
Patients should be informed that response to all
diabetic therapies should be monitored by periodic measurements of blood
glucose and A1C, with a goal of decreasing these levels toward the normal
range. A1C is especially useful for evaluating long-term glycemic control.
Patients should be informed of the potential need to adjust their dose based on
changes in renal function tests over time.
Onglyza is a registered trademark of the AstraZeneca group of companies.
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
Product of Ireland
|
MEDICATION GUIDE
Onglyza (on-GLY-zah)
(saxagliptin)
tablets, for oral use
|
|
What is the most important information I
should know about Onglyza?
Serious
side effects can happen to people taking Onglyza, including:
1) Inflammation of the
pancreas (pancreatitis) which may be severe and lead to death.
Certain medical problems
make you more likely to get pancreatitis.
Before
you start taking Onglyza:
Tell your healthcare
provider if you have ever had
|
|
•
inflammation
of your pancreas (pancreatitis)
•
a history of alcoholism
|
•
stones in
your gallbladder (gallstones)
•
high blood triglyceride levels
|
|
It
is not known if having these medical problems will make you more likely to
get pancreatitis with Onglyza.
Stop taking Onglyza and
contact your healthcare provider right away if you have pain in your stomach
area (abdomen) that is severe and will not go away. The pain may be felt
going from your abdomen through to your back. The pain may happen with or
without vomiting. These may be symptoms of pancreatitis.
2) Heart failure. Heart failure means your heart does not pump blood well enough.
Before
you start taking Onglyza:
Tell your healthcare
provider if you
•
have ever
had heart failure or have problems with your kidneys.
Contact
your healthcare provider 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.
|
|
What is Onglyza?
•
Onglyza is
a prescription medicine used with diet and exercise to control high blood
sugar (hyperglycemia) in adults with type 2 diabetes.
•
Onglyza
lowers blood sugar by helping the body increase the level of insulin after
meals.
•
Onglyza is
unlikely by itself to cause your blood sugar to be lowered to a dangerous
level (hypoglycemia) because it does not work well when your blood sugar is
low. However, hypoglycemia may still occur with Onglyza. Your risk for
getting hypoglycemia is higher if you take Onglyza with some other diabetes
medicines, such as a sulfonylurea or insulin.
•
Onglyza is
not for people with type 1 diabetes.
•
Onglyza is
not for people with diabetic ketoacidosis (increased ketones in your blood or
urine).
It is not
known if Onglyza is safe and effective in children younger than 18 years old.
|
|
Who should not take Onglyza?
Do
not take Onglyza if you:
•
are allergic to any ingredients in Onglyza. See
the end of this Medication Guide for a complete list of ingredients in
Onglyza.
Symptoms of a serious allergic reaction to Onglyza may include:
|
|
•
swelling
of your face, lips, throat, and other areas on your skin
•
raised, red areas on your skin (hives)
|
•
difficulty
with swallowing or breathing
•
skin rash, itching, flaking, or peeling
|
|
If
you have these symptoms, stop taking Onglyza and contact your healthcare
provider right away.
|
|
Before taking Onglyza tell your healthcare
provider about all of your medical conditions, including if you:
•
have
kidney problems.
•
are
pregnant or plan to become pregnant. It is not known if Onglyza will harm
your unborn baby. If you are pregnant, talk with your healthcare provider
about the best way to control your blood sugar while you are pregnant.
•
are
breast-feeding or plan to breast-feed. Onglyza may be passed in your milk to
your baby. Talk with your healthcare provider about the best way to feed your
baby while you take Onglyza.
Tell your healthcare provider about all the
medicines you take, including
prescription and over-the-counter medicines, vitamins, and herbal
supplements.
Know the
medicines you take. Keep a list of your medicines and show it to your
healthcare provider and pharmacist when you get a new medicine.
Onglyza
may affect the way other medicines work, and other medicines may affect how
Onglyza works. Contact your healthcare provider if you will be starting or
stopping certain other types of medications, such as antibiotics, or
medicines that treat fungus or HIV/AIDS, because your dose of Onglyza might
need to be changed.
|
|
How should I take Onglyza?
•
Take
Onglyza by mouth one time each day exactly as directed by your healthcare
provider. Do not change your dose without talking to your healthcare
provider.
•
Onglyza
can be taken with or without food.
•
Do not
split or cut Onglyza tablets.
•
During
periods of stress on the body, such as fever, trauma, infection, or surgery.
•
Contact
your healthcare provider right away as your medication needs may change.
•
Your
healthcare provider should test your blood to measure how well your kidneys
are working before and during your treatment with Onglyza. You may need a
lower dose of Onglyza if your kidneys are not working well.
•
Follow
your healthcare provider’s instructions for treating blood sugar that is too
low (hypoglycemia). Talk to your healthcare provider if low blood sugar is a
problem for you.
•
If you
miss a dose of Onglyza, take it as soon as you remember. If it is almost time
for your next dose, skip the missed dose. Just take the next dose at your
regular time. Do not take two doses at the same time unless your healthcare
provider tells you to do so. Talk to your healthcare provider if you have
questions about a missed dose.
•
If you take too much Onglyza, call your
healthcare provider or go to the nearest hospital emergency room right away.
|
|
What are the possible side effects of Onglyza?
Onglyza
can cause serious side effects, including:
•
See “What is the most important information I should know
about Onglyza?”
•
Allergic (hypersensitivity)
reactions,such as:
•
swelling
of your face, lips, throat, and other areas on your skin
•
difficulty
with swallowing or breathing
•
raised,
red areas on your skin (hives)
•
skin rash,
itching, flaking, or peeling
If you
have these symptoms, stop taking Onglyza and contact your healthcare provider
right away.
•
Joint pain. Some people who take medicines called DPP-4 inhibitors like Onglyza,
may develop joint pain that can be severe. Call your healthcare provider if
you have severe joint pain.
•
Skin reaction. Some
people who take medicines called DPP-4 inhibitors, like Onglyza, may develop
a skin reaction called bullous pemphigoid that can require treatment in a
hospital. Tell your healthcare provider right away if you develop blisters or
the breakdown of the outer layer of your skin (erosion). Your healthcare
provider may tell you to stop taking Onglyza.
Common side effects of Onglyza include:
•
upper
respiratory tract infection
•
urinary
tract infection
•
headache
Low blood sugar (hypoglycemia) may become worse in people who also take another medication to treat
diabetes, such as sulfonylureas or insulin. Tell your healthcare provider if
you take other diabetes medicines. If you have symptoms of low blood sugar,
you should check your blood sugar and treat if low, then call your healthcare
provider. Symptoms of low blood sugar include:
|
|
•
shaking
•
hunger
|
•
sweating
•
headache
|
•
rapid
heartbeat
•
change in mood
|
•
change in vision
|
|
Swelling or fluid retention in your hands, feet, or ankles (peripheral edema) may become worse in
people who also take a thiazolidinedione to treat diabetes. If you do not
know whether you are already on this type of medication, ask your healthcare
provider.
These are not all of the possible
side effects of Onglyza.
Call your doctor for
medical advice about side effects. You may report side effects to the FDA at
1-800-FDA-1088.
|
|
How should I store Onglyza?
Store Onglyza between 68°F to 77°F (20°C to 25°C).
Keep
Onglyza and all medicines out of the reach of children.
|
|
General information about the use of Onglyza
Medicines are sometimes
prescribed for conditions that are not mentioned in Medication Guides. Do not
use Onglyza for a condition for which it was not prescribed. Do not give
Onglyza to other people, even if they have the same symptoms you have. It may
harm them.
You can ask your
healthcare provider for additional information about Onglyza that is written
for health professionals.
|
|
What are the ingredients of Onglyza?
Active ingredient:
saxagliptin
Inactive ingredients:
lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and
magnesium stearate. In addition, the film coating contains the following
inactive ingredients: polyvinyl alcohol, polyethylene glycol, titanium
dioxide, talc, and iron oxides.
|
|
What is type 2 diabetes?
Type 2 diabetes is a
condition in which your body does not make enough insulin, and the insulin
that your body produces does not work as well as it should. Your body can
also make too much sugar. When this happens, sugar (glucose) builds up in the
blood. This can lead to serious medical problems.
The main goal of treating
diabetes is to lower your blood sugar so that it is as close to normal as
possible.
High blood sugar can be
lowered by diet and exercise, and by certain medicines when necessary.
|
|
Onglyza
is a registered trademark of the AstraZeneca group of companies. Distributed
by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850. For more information,
go to www.Onglyza.com or call 1-800-Onglyza.
|
|
This
Medication Guide has been approved by the U.S. Food and Drug Administration.
2/2017
|
|
|
|
|
|
Onglyza 5 mg Tablets Representative Packaging
See How
Supplied section for a complete list of available
packages of Onglyza.
30
Tablets
NDC 0310-6105-30
Onglyza®
(saxagliptin) tablets
5 mg
DISPENSE WITH MEDICATION GUIDE
Rx only
AstraZeneca
Onglyza 2.5 mg Tablets Representative Packaging
30
Tablets
NDC 0310-6100-30
Onglyza®
(saxagliptin) tablets
2.5 mg
DISPENSE WITH MEDICATION GUIDE
Rx only
AstraZeneca
|
Onglyza saxagliptin tablet, film coated
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0310-6105
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
saxagliptin hydrochloride (saxagliptin anhydrous)
|
saxagliptin
anhydrous
|
5 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
lactose monohydrate
|
|
|
cellulose, microcrystalline
|
|
|
croscarmellose sodium
|
|
|
magnesium stearate
|
|
|
|
Product
Characteristics
|
|
Color
|
PINK
|
Score
|
no score
|
|
Shape
|
ROUND
(biconvex)
|
Size
|
8mm
|
|
Flavor
|
|
Imprint Code
|
5;4215
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0310-6105-30
|
30 TABLET, FILM
COATED in 1 BOTTLE, PLASTIC
|
|
|
2
|
NDC:0310-6105-90
|
90 TABLET, FILM
COATED in 1 BOTTLE, PLASTIC
|
|
|
3
|
NDC:0310-6105-50
|
500 TABLET,
FILM COATED in 1 BOTTLE, PLASTIC
|
|
|
4
|
NDC:0310-6105-95
|
1 BLISTER PACK
in 1 CARTON
|
|
|
4
|
|
7 TABLET, FILM
COATED in 1 BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA022350
|
11/20/2014
|
|
|
|
Onglyza saxagliptin tablet, film coated
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0310-6100
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
saxagliptin hydrochloride (saxagliptin anhydrous)
|
saxagliptin
anhydrous
|
2.5 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
lactose monohydrate
|
|
|
cellulose, microcrystalline
|
|
|
croscarmellose sodium
|
|
|
magnesium stearate
|
|
|
|
Product
Characteristics
|
|
Color
|
YELLOW (pale
yellow to light yellow)
|
Score
|
no score
|
|
Shape
|
ROUND
(biconvex)
|
Size
|
8mm
|
|
Flavor
|
|
Imprint Code
|
2;5;4214
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0310-6100-30
|
30 TABLET, FILM
COATED in 1 BOTTLE, PLASTIC
|
|
|
2
|
NDC:0310-6100-90
|
90 TABLET, FILM
COATED in 1 BOTTLE, PLASTIC
|
|
|
3
|
NDC:0310-6100-95
|
1 BLISTER PACK
in 1 CARTON
|
|
|
3
|
|
7 TABLET, FILM
COATED in 1 BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA022350
|
11/20/2014
|
|
|
|
Labeler - AstraZeneca Pharmaceuticals LP
(054743190)
|
|
Registrant - AstraZeneca PLC (230790719)
|
Revised: 02/2017
AstraZeneca
Pharmaceuticals LP
