Overdose
Saxagliptin
In a controlled clinical trial,
once-daily, orally administered saxagliptin 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).
Metformin Hydrochloride
Overdose of metformin
hydrochloride has occurred, including ingestion of amounts greater than 50
grams. Hypoglycemia was reported in approximately 10% of cases, but no causal
association with metformin hydrochloride has been established. Lactic acidosis
has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170
mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful
for removal of accumulated drug from patients in whom metformin overdosage is
suspected.
Contraindications
KOMBIGLYZE XR is
contraindicated in patients with:
- Renal impairment (e.g., serum
creatinine levels ≥ 1.5 mg/dL for men, ≥ 1.4 mg/dL for women, or
abnormal creatinine clearance) which may also result from conditions such as
cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
- Hypersensitivity to metformin
hydrochloride.
- Acute or chronic metabolic
acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be
treated with insulin.
- History of a serious
hypersensitivity reaction to KOMBIGLYZE XR or saxagliptin, such as anaphylaxis,
angioedema, or exfoliative skin conditions.
Undesirable effects
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 with
Monotherapy and with Add-On Combination Therapy
Metformin Hydrochloride
In placebo-controlled
monotherapy trials of metformin extended-release, diarrhea and nausea/vomiting
were reported in > 5% of metformin-treated patients and more commonly than in
placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5%
for nausea/vomiting). Diarrhea led to discontinuation of study medication in
0.6% of the patients treated with metformin extended-release.
Saxagliptin
In two placebo-controlled
monotherapy trials of 24-week duration, patients were treated with saxagliptin
2.5 mg daily, saxagliptin 5 mg daily, and placebo. Three 24-week,
placebo-controlled, add-on combination therapy trials were also conducted: one
with metformin immediate-release, one with a thiazolidinedione (pioglitazone or
rosiglitazone), and one with glyburide. In these three trials, patients were
randomized to add-on therapy with saxagliptin 2.5 mg daily, saxagliptin 5 mg
daily, or placebo.
A saxagliptin 10 mg treatment
arm was included in one of the monotherapy trials and in the add-on combination
trial with metformin immediate-release. The 10 mg saxagliptin dosage is not an
approved dosage.
In a pre-specified pooled
analysis of the 24-week data (regardless of glycemic rescue) from the two
monotherapy trials, the add-on to metformin immediate-release trial, the add-on
to thiazolidinedione (TZD) trial, and the add-on to glyburide trial, the
overall incidence of adverse events in patients treated with saxagliptin 2.5 mg
and saxagliptin 5 mg was similar to placebo (72% and 72.2% versus 70.6%,
respectively). Discontinuation of therapy due to adverse events occurred in 2.2%,
3.3%, and 1.8% of patients receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and
placebo, respectively. The most common adverse events (reported in at least 2
patients treated with saxagliptin 2.5 mg or at least 2 patients treated with
saxagliptin 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%). The adverse reactions in
this pooled analysis reported (regardless of investigator assessment of
causality) in ≥ 5% of patients treated with saxagliptin 5 mg, and more
commonly than in patients treated with placebo are shown in Table 1.
Table 1: Adverse Reactions
in Placebo-Controlled Trials* Reported in ≥ 5% of Patients Treated with
Saxagliptin 5 mg and More Commonly than in Patients Treated with Placebo
| |
Number (%) of Patients |
Saxagliptin 5 mg
N=882 |
Placebo
N=799 |
| Upper respiratory tract infection |
68 (7.7) |
61 (7.6) |
| Urinary tract infection |
60 (6.8) |
49 (6.1) |
| Headache |
57 (6.5) |
47 (5.9) |
| * 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. |
In patients treated with
saxagliptin 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 this pooled analysis,
adverse reactions that were reported in ≥ 2% of patients treated with
saxagliptin 2.5 mg or saxagliptin 5 mg and ≥ 1% more frequently compared
to placebo included: sinusitis (2.9% and 2.6% versus 1.6%, respectively),
abdominal pain (2.4% and 1.7% versus 0.5%), gastroenteritis (1.9% and 2.3%
versus 0.9%), and vomiting (2.2% and 2.3% versus 1.3%).
The incidence rate of fractures
was 1.0 and 0.6 per 100 patient-years, respectively, for saxagliptin (pooled
analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The 10 mg saxagliptin dosage
is not an approved dosage. The incidence rate of fracture events in patients
who received saxagliptin did not increase over time. Causality has not been
established and nonclinical studies have not demonstrated adverse effects of
saxagliptin 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 saxagliptin
is not known.
Adverse Reactions with
Concomitant Use with Insulin
In the add-on to insulin trial
, the incidence of adverse events, including
serious adverse events and discontinuations due to adverse events, was similar
between saxagliptin and placebo, except for confirmed hypoglycemia.
Adverse Reactions Associated
with Saxagliptin Coadministered with Metformin Immediate-Release in
Treatment-Naive Patients with Type 2 Diabetes
Table 2 shows the adverse
reactions reported (regardless of investigator assessment of causality) in
≥ 5% of patients participating in an additional 24-week, active-controlled
trial of coadministered saxagliptin and metformin in treatment-naive patients.
Table 2: Coadministration of
Saxagliptin and Metformin Immediate-Release in Treatment-Naive Patients:
Adverse Reactions Reported in ≥ 5% of Patients Treated with Combination
Therapy of Saxagliptin 5 mg Plus Metformin Immediate-Release (and More Commonly
than in Patients Treated with Metformin Immediate-Release Alone)
| |
Number(%) of Patients |
Saxagliptin 5 mg + Metformin*
N=320 |
Placebo + Metformin*
N=328 |
| Headache |
24 (7.5) |
17 (5.2) |
| Nasopharyngitis |
22 (6.9) |
13 (4.0) |
| * Metformin immediate-release
was initiated at a starting dose of 500 mg daily and titrated up to a maximum
of 2000 mg daily. |
In patients treated with the
combination of saxagliptin and metformin immediate-release, either as
saxagliptin add-on to metformin immediate-release therapy or as
coadministration in treatment-naive patients, diarrhea was the only
gastrointestinal-related event that occurred with an incidence ≥ 5% in any
treatment group in both studies. In the saxagliptin add-on to metformin
immediate-release trial, the incidence of diarrhea was 9.9%, 5.8%, and 11.2% in
the saxagliptin 2.5 mg, 5 mg, and placebo groups, respectively. When
saxagliptin and metformin immediate-release were coadministered in treatment-naive
patients, the incidence of diarrhea was 6.9% in the saxagliptin 5 mg +
metformin immediate-release group and 7.3% in the placebo + metformin
immediate-release group.
Hypoglycemia
In the saxagliptin clinical
trials, 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.
The incidence of reported
hypoglycemia for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo given
as monotherapy was 4% and 5.6% versus 4.1%, respectively. In the add-on to
metformin immediate-release trial, the incidence of reported hypoglycemia was
7.8% with saxagliptin 2.5 mg, 5.8% with saxagliptin 5 mg, and 5% with placebo.
When saxagliptin and metformin immediate-release were coadministered in
treatment-naive patients, the incidence of reported hypoglycemia was 3.4% in
patients given saxagliptin 5 mg + metformin immediate-release and 4% in
patients given placebo + metformin immediate-release.
In the active-controlled trial
comparing add-on therapy with saxagliptin 5 mg to glipizide in patients
inadequately controlled on metformin alone, the incidence of reported hypoglycemia
was 3% (19 events in 13 patients) with saxagliptin 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 saxagliptin-treated patients and in 35 glipizide-treated patients (8.1%)
(p < 0.0001).
In the saxagliptin add-on to
insulin trial, the overall incidence of reported hypoglycemia was 18.4% for
saxagliptin 5 mg and 19.9% for placebo. However, the incidence of confirmed
symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤ 50
mg/dL) was higher with saxagliptin 5 mg (5.3%) versus placebo (3.3%). Among the
patients using insulin in combination with metformin, the incidence of
confirmed symptomatic hypoglycemia was 4.8% with saxagliptin versus 1.9% with
placebo.
In the saxagliptin add-on to
metformin plus sulfonylurea trial, the overall incidence of reported
hypoglycemia was 10.1% for saxagliptin 5 mg and 6.3% for placebo. Confirmed
hypoglycemia was reported in 1.6% of the saxagliptin-treated patients and in
none of the placebo-treated patients.
Hypersensitivity Reactions
Saxagliptin
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
saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. None of these
events in patients who received saxagliptin required hospitalization or were
reported as life-threatening by the investigators. One saxagliptin-treated
patient in this pooled analysis discontinued due to generalized urticaria and
facial edema.
Infections
Saxagliptin
In the unblinded, controlled,
clinical trial database for saxagliptin to date, there have been 6 (0.12%)
reports of tuberculosis among the 4959 saxagliptin-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 the
United States or in Western Europe. One case occurred in Canada in a patient
originally from Indonesia who had recently visited Indonesia. The duration of
treatment with saxagliptin 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
saxagliptin that remained stable throughout saxagliptin 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 saxagliptin use. Causality has not been
established and there are too few cases to date to determine whether
tuberculosis is related to saxagliptin use.
There has been one case of a
potential opportunistic infection in the unblinded, controlled clinical trial
database to date in a saxagliptin-treated patient who developed suspected
foodborne fatal salmonella sepsis after approximately 600 days of saxagliptin
therapy. There have been no spontaneous reports of opportunistic infections
associated with saxagliptin use.
Vital Signs
Saxagliptin
No clinically meaningful changes in vital signs have been
observed in patients treated with saxagliptin alone or in combination with
metformin.
Laboratory Tests
Absolute Lymphocyte Counts
Saxagliptin
There was a dose-related mean decrease in absolute
lymphocyte count observed with saxagliptin. From a baseline mean absolute
lymphocyte count of approximately 2200 cells/microL, mean decreases of
approximately 100 and 120 cells/microL with saxagliptin 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 saxagliptin 5 mg and metformin were coadministered in
treatment-naive patients compared to placebo and metformin. There was no
difference observed for saxagliptin 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 saxagliptin 2.5 mg, 5 mg, 10
mg, and placebo groups, respectively. In most patients, recurrence was not
observed with repeated exposure to saxagliptin although some patients had
recurrent decreases upon rechallenge that led to discontinuation of
saxagliptin. The decreases in lymphocyte count were not associated with
clinically relevant adverse reactions. The 10 mg saxagliptin dosage is not an
approved dosage.
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 saxagliptin on lymphocyte counts in patients with
lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.
Vitamin B12 Concentrations
Metformin Hydrochloride
Metformin may lower serum vitamin B12 concentrations.
Measurement of hematologic parameters on an annual basis is advised in patients
on KOMBIGLYZE XR and any apparent abnormalities should be appropriately
investigated and managed.
Postmarketing Experience
Additional adverse reactions have been identified during
postapproval use of saxagliptin. 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.
- Acute pancreatitis.
- Severe and disabling arthralgia.
Therapeutic indications
KOMBIGLYZE XR is indicated as
an adjunct to diet and exercise to improve glycemic control in adults with type
2 diabetes mellitus when treatment with both saxagliptin and metformin is
appropriate.
Limitation Of Use
KOMBIGLYZE XR should not be
used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
KOMBIGLYZE XR has not been
studied in patients with a history of pancreatitis. It is unknown whether
patients with a history of pancreatitis are at an increased risk for the
development of pancreatitis while using KOMBIGLYZE XR.
Pharmacodynamic properties
Saxagliptin
In patients with type 2
diabetes mellitus, administration of saxagliptin 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
Saxagliptin
In a randomized, double-blind,
placebo-controlled, 4-way crossover, active comparator study using moxifloxacin
in 40 healthy subjects, saxagliptin 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).
Pharmacokinetic properties
KOMBIGLYZE XR
Bioequivalence and food effect
of KOMBIGLYZE XR was characterized under low calorie diet. The low calorie diet
consisted of 324 kcal with meal composition that contained 11.1% protein, 10.5%
fat, and 78.4% carbohydrate. The results of bioequivalence studies in healthy
subjects demonstrated that KOMBIGLYZE XR combination tablets are bioequivalent
to coadministration of corresponding doses of saxagliptin (ONGLYZA®) and metformin hydrochloride extended-release (GLUCOPHAGE®
XR) as individual tablets under fed
conditions.
Saxagliptin
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 Cmax values 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.
Metformin Hydrochloride
Metformin extended-release Cmax
is achieved with a median value of 7
hours and a range of 4 to 8 hours. At steady state, the AUC and Cmax
are less than dose proportional for
metformin extended-release within the range of 500 to 2000 mg. After repeated
administration of metformin extended-release, metformin did not accumulate in
plasma. Metformin is excreted unchanged in the urine and does not undergo
hepatic metabolism. Peak plasma levels of metformin extended-release tablets
are approximately 20% lower compared to the same dose of metformin
immediate-release tablets, however, the extent of absorption (as measured by
AUC) is similar between extended-release tablets and immediate-release tablets.
Absorption
Saxagliptin
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. Saxagliptin may be administered with or without food.
Food has no significant effect on the pharmacokinetics of saxagliptin when
administered as KOMBIGLYZE XR combination tablets.
Metformin Hydrochloride
Following a single oral dose of
metformin extended-release, Cmax is achieved with a median value of 7 hours and a range of 4
to 8 hours. Although the extent of metformin absorption (as measured by AUC)
from the metformin extended-release tablet increased by approximately 50% when
given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same
effect on the pharmacokinetics of metformin extended-release. Food has no
significant effect on the pharmacokinetics of metformin when administered as
KOMBIGLYZE XR combination tablets.
Distribution
Saxagliptin
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.
Metformin Hydrochloride
Distribution studies with
extended-release metformin have not been conducted; however, the apparent
volume of distribution (V/F) of metformin following single oral doses of
immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is
negligibly bound to plasma proteins, in contrast to sulfonylureas, which are
more than 90% protein bound. Metformin partitions into erythrocytes, most
likely as a function of time. Metformin is negligibly bound to plasma proteins
and is, therefore, less likely to interact with highly protein-bound drugs such
as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to
the sulfonylureas, which are extensively bound to serum proteins.
Metabolism
Saxagliptin
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.
Metformin Hydrochloride
Intravenous single-dose studies
in healthy subjects demonstrate that metformin is excreted unchanged in the
urine and does not undergo hepatic metabolism (no metabolites have been
identified in humans) or biliary excretion.
Metabolism studies with
extended-release metformin tablets have not been conducted.
Excretion
Saxagliptin
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 saxagliptin 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.
Metformin Hydrochloride
Renal clearance is
approximately 3.5 times greater than creatinine clearance, which indicates that
tubular secretion is the major route of metformin elimination. Following oral
administration, approximately 90% of the absorbed drug is eliminated via the
renal route within the first 24 hours, with a plasma elimination half-life of
approximately 6.2 hours. In blood, the elimination half-life is approximately
17.6 hours, suggesting that the erythrocyte mass may be a compartment of
distribution.
Date of revision of the text
August 2015
Name of the medicinal product
Kombiglyze XR
Fertility, pregnancy and lactation
Pregnancy Category B
There are no adequate and well-controlled studies in
pregnant women with KOMBIGLYZE XR or its individual components. Because animal
reproduction studies are not always predictive of human response, KOMBIGLYZE
XR, like other antidiabetic medications, should be used during pregnancy only
if clearly needed.
Coadministration of saxagliptin and metformin, to
pregnant rats and rabbits during the period of organogenesis, was neither
embryolethal nor teratogenic in either species when tested at doses yielding
systemic exposures (AUC) up to 100 and 10 times the maximum recommended human
doses (MRHD; saxagliptin 5 mg and metformin 2000 mg), respectively, in rats;
and 249 and 1.1 times the MRHDs in rabbits. In rats, minor developmental
toxicity was limited to an increased incidence of wavy ribs; associated
maternal toxicity was limited to weight decrements of 11% to 17% over the
course of the study, and related reductions in maternal food consumption. In
rabbits, coadministration was poorly tolerated in a subset of mothers (12 of
30), resulting in death, moribundity, or abortion. However, among surviving
mothers with evaluable litters, maternal toxicity was limited to marginal
reductions in body weight over the course of gestation days 21 to 29; and
associated developmental toxicity in these litters was limited to fetal body
weight decrements of 7%, and a low incidence of delayed ossification of the
fetal hyoid.
Saxagliptin
Saxagliptin was not teratogenic at any dose tested when administered
to pregnant rats and rabbits during periods of organogenesis. Incomplete
ossification of the pelvis, a form of developmental delay, occurred in rats at
a dose of 240 mg/kg, or approximately 1503 and 66 times human exposure to
saxagliptin and the active metabolite, respectively, at the MRHD of 5 mg.
Maternal toxicity and reduced fetal body weights were observed at 7986 and 328
times the human exposure at the MRHD for saxagliptin and the active metabolite,
respectively. Minor skeletal variations in rabbits occurred at a maternally
toxic dose of 200 mg/kg, or approximately 1432 and 992 times the MRHD.
Saxagliptin administered to female rats from gestation
day 6 to lactation day 20 resulted in decreased body weights in male and female
offspring only at maternally toxic doses (exposures ≥ 1629 and 53 times
saxagliptin and its active metabolite at the MRHD). No functional or behavioral
toxicity was observed in offspring of rats administered saxagliptin at any
dose.
Saxagliptin crosses the placenta into the fetus following
dosing in pregnant rats.
Metformin Hydrochloride
Metformin was not teratogenic in rats and rabbits at
doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times
the maximum recommended human daily dose of 2000 mg based on body surface area
comparisons for rats and rabbits, respectively. Determination of fetal
concentrations demonstrated a partial placental barrier to metformin.
Qualitative and quantitative composition
Dosage Forms And Strengths
- KOMBIGLYZE XR (saxagliptin and
metformin HCl extended-release) 5 mg/500 mg tablets are light brown to brown,
biconvex, capsule-shaped, film-coated tablets with “5/500” printed on one side
and “4221” printed on the reverse side, in blue ink.
- KOMBIGLYZE XR (saxagliptin and
metformin HCl extended-release) 5 mg/1000 mg tablets are pink, biconvex,
capsule-shaped, film-coated tablets with “5/1000” printed on one side and
“4223” printed on the reverse side, in blue ink.
- KOMBIGLYZE XR (saxagliptin and
metformin HCl extended-release) 2.5 mg/1000 mg tablets are pale yellow to light
yellow, biconvex, capsule-shaped, film-coated tablets with “2.5/1000” printed
on one side and “4222” printed on the reverse side, in blue ink.
KOMBIGLYZE® XR (saxagliptin and metformin HCl
extended-release) tablets have markings on both sides and are available in the
strengths and packages listed in Table 12
Table 12: KOMBIGLYZE XR Tablet Presentations
| Tablet Strength (saxagliptin and metformin HCl extended-release) |
Film-Coated Tablet Color/Shape |
Tablet Markings |
Package Size |
NDC Code |
| 5 mg/500 mg |
light brown to brown, biconvex, capsuleshaped |
“5/500” on one side and “4221” on the reverse, in blue ink |
Bottles of 30 |
0310-6135-30 |
| 5 mg/1000 mg |
pink, biconvex, capsule- shaped |
“5/1000” on one side and “4223” on the reverse, in blue ink |
Bottles of 30 |
0310-6145-30 |
| 2.5 mg/1000 mg |
pale yellow to light yellow, biconvex, capsuleshaped |
“2.5/1000” on one side and “4222” on the reverse, in blue ink |
Bottles of 60 |
0310-6125-60 |
Storage And Handling
Store at 20°C to 25°C (68°F to 77°F); excursions
permitted between 15°C and 30°C (59°F and 86°F).
Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington,
DE 19850. Revised: August 2015
Special warnings and precautions for use
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Lactic Acidosis
Lactic acidosis is a rare, but
serious, metabolic complication that can occur due to metformin accumulation
during treatment with KOMBIGLYZE XR; when it occurs, it is fatal in
approximately 50% of cases. Lactic acidosis may also occur in association with
a number of pathophysiologic conditions, including diabetes mellitus, and
whenever there is significant tissue hypoperfusion and hypoxemia. Lactic
acidosis is characterized by elevated blood lactate levels ( > 5 mmol/L),
decreased blood pH, electrolyte disturbances with an increased anion gap, and
an increased lactate/ pyruvate ratio. When metformin is implicated as the cause
of lactic acidosis, metformin plasma levels > 5 μg/mL are generally
found.
The reported incidence of
lactic acidosis in patients receiving metformin hydrochloride is very low
(approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal
cases/1000 patient-years). In more than 20,000 patient-years exposure to
metformin in clinical trials, there were no reports of lactic acidosis.
Reported cases have occurred primarily in diabetic patients with significant
renal insufficiency, including both intrinsic renal disease and renal
hypoperfusion, often in the setting of multiple concomitant medical/surgical
problems and multiple concomitant medications. Patients with congestive heart
failure requiring pharmacologic management, in particular those with unstable
or acute congestive heart failure who are at risk of hypoperfusion and
hypoxemia, are at increased risk of lactic acidosis. The risk of lactic
acidosis increases with the degree of renal dysfunction and the patient's age.
The risk of lactic acidosis may, therefore, be significantly decreased by
regular monitoring of renal function in patients taking metformin and by use of
the minimum effective dose of metformin. In particular, treatment of the
elderly should be accompanied by careful monitoring of renal function.
Metformin treatment should not be initiated in patients ≥ 80 years of age
unless measurement of creatinine clearance demonstrates that renal function is
not reduced, as these patients are more susceptible to developing lactic
acidosis. In addition, metformin should be promptly withheld in the presence of
any condition associated with hypoxemia, dehydration, or sepsis. Because
impaired hepatic function may significantly limit the ability to clear lactate,
metformin should generally be avoided in patients with clinical or laboratory
evidence of hepatic disease. Patients should be cautioned against excessive
alcohol intake when taking metformin since alcohol potentiates the effects of
metformin hydrochloride on lactate metabolism. In addition, metformin should be
temporarily discontinued prior to any intravascular radiocontrast study and for
any surgical procedure.
The onset of lactic acidosis
often is subtle and accompanied only by nonspecific symptoms such as malaise,
myalgias, respiratory distress, increasing somnolence, and nonspecific
abdominal distress. There may be associated hypothermia, hypotension, and
resistant bradyarrhythmias with more marked acidosis. The patient and the
patient's physician must be aware of the possible importance of such symptoms
and the patient should be instructed to notify the physician immediately if
they occur. Metformin should be withdrawn
until the situation is clarified. Serum electrolytes, ketones, blood glucose,
and if indicated, blood pH, lactate levels, and even blood metformin levels may
be useful. Once a patient is stabilized on any dose level of metformin,
gastrointestinal symptoms, which are common during initiation of therapy, are
unlikely to be drug related. Later occurrence of gastrointestinal symptoms
could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma
lactate above the upper limit of normal, but less than 5 mmol/L, in patients
taking metformin do not necessarily indicate impending lactic acidosis and may
be explainable by other mechanisms, such as poorly controlled diabetes or
obesity, vigorous physical activity, or technical problems in sample handling
.
Lactic acidosis should be
suspected in any diabetic patient with metabolic acidosis lacking evidence of
ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical
emergency that must be treated in a hospital setting. In a patient with lactic
acidosis who is taking metformin, the drug should be discontinued immediately
and general supportive measures promptly instituted. Because metformin
hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good
hemodynamic conditions), prompt hemodialysis is recommended to correct the
acidosis and remove the accumulated metformin. Such management often results in
prompt reversal of symptoms and recovery.
Pancreatitis
There have been postmarketing
reports of acute pancreatitis in patients taking saxagliptin. After initiation
of KOMBIGLYZE XR, patients should be observed carefully for signs and symptoms
of pancreatitis. If pancreatitis is suspected, KOMBIGLYZE XR should promptly be
discontinued and appropriate management should be initiated. It is unknown
whether patients with a history of pancreatitis are at increased risk for the
development of pancreatitis while using KOMBIGLYZE XR.
Assessment Of Renal Function
Metformin is substantially
excreted by the kidney, and the risk of metformin accumulation and lactic
acidosis increases with the degree of impairment of renal function. Therefore,
KOMBIGLYZE XR is contraindicated in patients with renal impairment.
Before initiation of KOMBIGLYZE
XR, and at least annually thereafter, renal function should be assessed and
verified as normal. In patients in whom development of renal impairment is
anticipated (e.g., elderly), renal function should be assessed more frequently
and KOMBIGLYZE XR discontinued if evidence of renal impairment is present.
Impaired Hepatic Function
Metformin use in patients with
impaired hepatic function has been associated with some cases of lactic
acidosis. Therefore, KOMBIGLYZE XR is not recommended in patients with hepatic
impairment.
Vitamin B12 Concentrations
In controlled clinical trials
of metformin of 29-week duration, a decrease to subnormal levels of previously
normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately
7% of patients. Such decrease, possibly due to interference with B12
absorption from the B12-intrinsic factor complex, is, however, very rarely
associated with anemia and appears to be rapidly reversible with
discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on
an annual basis is advised in patients on KOMBIGLYZE XR and any apparent
abnormalities should be appropriately investigated and managed.
Certain individuals (those with
inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing
subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.
Alcohol Intake
Alcohol potentiates the effect
of metformin on lactate metabolism. Patients should be warned against excessive
alcohol intake while receiving KOMBIGLYZE XR.
Surgical Procedures
Use of KOMBIGLYZE XR should be
temporarily suspended for any surgical procedure (except minor procedures not
associated with restricted intake of food and fluids) and should not be
restarted until the patient's oral intake has resumed and renal function has
been evaluated as normal.
Change In Clinical Status Of Patients
With Previously Controlled Type 2 Diabetes
A patient with type 2 diabetes
previously well controlled on KOMBIGLYZE XR who develops laboratory
abnormalities or clinical illness (especially vague and poorly defined illness)
should be evaluated promptly for evidence of ketoacidosis or lactic acidosis.
Evaluation should include serum electrolytes and ketones, blood glucose and, if
indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of
either form occurs, KOMBIGLYZE XR must be stopped immediately and other
appropriate corrective measures initiated.
Hypoglycemia With Concomitant
Use Of Sulfonylurea Or Insulin
Saxagliptin
When saxagliptin 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. Therefore, a lower dose of the insulin secretagogue or
insulin may be required to minimize the risk of hypoglycemia when used in
combination with KOMBIGLYZE XR.
Metformin hydrochloride
Hypoglycemia does not occur in
patients receiving metformin alone under usual circumstances of use, but could
occur when caloric intake is deficient, when strenuous exercise is not
compensated by caloric supplementation, or during concomitant use with other
glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.
Elderly, debilitated, or malnourished patients and those with adrenal or
pituitary insufficiency or alcohol intoxication are particularly susceptible to
hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly
and in people who are taking beta-adrenergic blocking drugs.
Concomitant Medications
Affecting Renal Function Or Metformin Disposition
Concomitant medication(s) that
may affect renal function or result in significant hemodynamic change or may
interfere with the disposition of metformin, such as cationic drugs that are
eliminated by renal tubular secretion , should be
used with caution.
Radiologic Studies With Intravascular
Iodinated Contrast Materials
Intravascular contrast studies
with iodinated materials can lead to acute alteration of renal function and
have been associated with lactic acidosis in patients receiving metformin.
Therefore, in patients in whom any such study is planned, KOMBIGLYZE XR should
be temporarily discontinued at the time of or prior to the procedure, and
withheld for 48 hours subsequent to the procedure and reinstituted only after
renal function has been re-evaluated and found to be normal.
Hypoxic States
Cardiovascular collapse
(shock), acute congestive heart failure, acute myocardial infarction, and other
conditions characterized by hypoxemia have been associated with lactic acidosis
and may also cause prerenal azotemia. When such events occur in patients on
KOMBIGLYZE XR therapy, the drug should be promptly discontinued.
Hypersensitivity Reactions
There have been postmarketing
reports of serious hypersensitivity reactions in patients treated with
saxagliptin. These reactions include anaphylaxis, angioedema, and exfoliative
skin conditions. Onset of these reactions occurred within the first 3 months
after initiation of treatment with saxagliptin, with some reports occurring
after the first dose. If a serious hypersensitivity reaction is suspected,
discontinue KOMBIGLYZE XR, assess for other potential causes for the event, and
institute alternative treatment for diabetes.
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 KOMBIGLYZE XR.
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.
Macrovascular Outcomes
There have been no clinical
studies establishing conclusive evidence of macrovascular risk reduction with
KOMBIGLYZE XR or any other antidiabetic drug.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Medication Guide
Healthcare providers should instruct their patients to
read the Medication Guide before starting KOMBIGLYZE XR 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 KOMBIGLYZE XR 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.
Lactic Acidosis
The risks of lactic acidosis due to the metformin
component, its symptoms and conditions that predispose to its development, as
noted in Warnings and Precautions (5.1), should be explained to patients.
Patients should be advised to discontinue KOMBIGLYZE XR immediately and to
promptly notify their healthcare provider if unexplained hyperventilation,
myalgia, malaise, unusual somnolence, dizziness, slow or irregular heartbeat,
sensation of feeling cold (especially in the extremities), or other nonspecific
symptoms occur. Gastrointestinal symptoms are common during initiation of
metformin treatment and may occur during initiation of KOMBIGLYZE XR therapy;
however, patients should consult their physician if they develop unexplained
symptoms. Although gastrointestinal symptoms that occur after stabilization are
unlikely to be drug related, such an occurrence of symptoms should be evaluated
to determine if it may be due to lactic acidosis or other serious disease.
Patients should be counseled against excessive alcohol
intake while receiving KOMBIGLYZE XR.
Patients should be informed about the importance of
regular testing of renal function and hematological parameters when receiving
treatment with KOMBIGLYZE XR.
Pancreatitis
Patients should be informed that acute pancreatitis has
been reported during postmarketing use of saxagliptin. Before initiating
KOMBIGLYZE XR, 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 KOMBIGLYZE XR and contact
their physician if persistent severe abdominal pain occurs.
Hypoglycemia
Patients should be informed that the incidence of
hypoglycemia may be increased when KOMBIGLYZE XR is added to an insulin
secretagogue (e.g., sulfonylurea) or insulin.
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 saxagliptin. 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 KOMBIGLYZE XR 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.
Administration Instructions
Patients should be informed that KOMBIGLYZE XR must be
swallowed whole and not crushed or chewed, and that the inactive ingredients
may occasionally be eliminated in the feces as a soft mass that may resemble
the original tablet.
Missed Dose
Patients should be informed that if they miss a dose of
KOMBIGLYZE XR, 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.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
KOMBIGLYZE XR
No animal studies have been conducted with KOMBIGLYZE XR
to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The
following data are based on the findings in the studies with saxagliptin and
metformin individually.
Saxagliptin
Saxagliptin did not induce tumors in either mice (50,
250, and 600 mg/kg) or rats (25, 75, 150, and 300 mg/kg) at the highest doses
evaluated. The highest doses evaluated in mice were equivalent to approximately
870 (males) and 1165 (females) times the human exposure at the MRHD of 5
mg/day. In rats, exposures were approximately 355 (males) and 2217 (females)
times the MRHD.
Metformin Hydrochloride
Long-term carcinogenicity studies have been performed in
rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at
doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These
doses are both approximately 4 times the maximum recommended human daily dose
of 2000 mg based on body surface area comparisons. No evidence of
carcinogenicity with metformin was found in either male or female mice.
Similarly, there was no tumorigenic potential observed with metformin in male
rats. There was, however, an increased incidence of benign stromal uterine
polyps in female rats treated with 900 mg/kg/day.
Mutagenesis
Saxagliptin
Saxagliptin was not mutagenic or clastogenic with or
without metabolic activation in an in vitro Ames bacterial assay, an in vitro
cytogenetics assay in primary human lymphocytes, an in vivo oral micronucleus
assay in rats, an in vivo oral DNA repair study in rats, and an oral in vivo/in
vitro cytogenetics study in rat peripheral blood lymphocytes. The active
metabolite was not mutagenic in an in vitro Ames bacterial assay.
Metformin Hydrochloride
There was no evidence of a mutagenic potential of
metformin in the following in vitro tests: Ames test (S. typhimurium), gene
mutation test (mouse lymphoma cells), or chromosomal aberrations test (human
lymphocytes). Results in the in vivo mouse micronucleus test were also
negative.
Impairment of Fertility
Saxagliptin
In a rat fertility study, males were treated with oral
gavage doses for 2 weeks prior to mating, during mating, and up to scheduled
termination (approximately 4 weeks total) and females were treated with oral
gavage doses for 2 weeks prior to mating through gestation day 7. No adverse effects
on fertility were observed at exposures of approximately 603 (males) and 776
(females) times the MRHD. Higher doses that elicited maternal toxicity also
increased fetal resorptions (approximately 2069 and 6138 times the MRHD).
Additional effects on estrous cycling, fertility, ovulation, and implantation
were observed at approximately 6138 times the MRHD.
Metformin Hydrochloride
Fertility of male or female rats was unaffected by
metformin when administered at doses as high as 600 mg/kg/day, which is
approximately 3 times the maximum recommended human daily dose based on body
surface area comparisons.
Use In Specific Populations
Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies in
pregnant women with KOMBIGLYZE XR or its individual components. Because animal
reproduction studies are not always predictive of human response, KOMBIGLYZE
XR, like other antidiabetic medications, should be used during pregnancy only
if clearly needed.
Coadministration of saxagliptin and metformin, to
pregnant rats and rabbits during the period of organogenesis, was neither
embryolethal nor teratogenic in either species when tested at doses yielding
systemic exposures (AUC) up to 100 and 10 times the maximum recommended human
doses (MRHD; saxagliptin 5 mg and metformin 2000 mg), respectively, in rats;
and 249 and 1.1 times the MRHDs in rabbits. In rats, minor developmental
toxicity was limited to an increased incidence of wavy ribs; associated
maternal toxicity was limited to weight decrements of 11% to 17% over the
course of the study, and related reductions in maternal food consumption. In
rabbits, coadministration was poorly tolerated in a subset of mothers (12 of
30), resulting in death, moribundity, or abortion. However, among surviving
mothers with evaluable litters, maternal toxicity was limited to marginal
reductions in body weight over the course of gestation days 21 to 29; and
associated developmental toxicity in these litters was limited to fetal body
weight decrements of 7%, and a low incidence of delayed ossification of the
fetal hyoid.
Saxagliptin
Saxagliptin was not teratogenic at any dose tested when administered
to pregnant rats and rabbits during periods of organogenesis. Incomplete
ossification of the pelvis, a form of developmental delay, occurred in rats at
a dose of 240 mg/kg, or approximately 1503 and 66 times human exposure to
saxagliptin and the active metabolite, respectively, at the MRHD of 5 mg.
Maternal toxicity and reduced fetal body weights were observed at 7986 and 328
times the human exposure at the MRHD for saxagliptin and the active metabolite,
respectively. Minor skeletal variations in rabbits occurred at a maternally
toxic dose of 200 mg/kg, or approximately 1432 and 992 times the MRHD.
Saxagliptin administered to female rats from gestation
day 6 to lactation day 20 resulted in decreased body weights in male and female
offspring only at maternally toxic doses (exposures ≥ 1629 and 53 times
saxagliptin and its active metabolite at the MRHD). No functional or behavioral
toxicity was observed in offspring of rats administered saxagliptin at any
dose.
Saxagliptin crosses the placenta into the fetus following
dosing in pregnant rats.
Metformin Hydrochloride
Metformin was not teratogenic in rats and rabbits at
doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times
the maximum recommended human daily dose of 2000 mg based on body surface area
comparisons for rats and rabbits, respectively. Determination of fetal
concentrations demonstrated a partial placental barrier to metformin.
Nursing Mothers
No studies in lactating animals have been conducted with
the combined components of KOMBIGLYZE XR. In studies performed with the
individual components, both saxagliptin and metformin are secreted in the milk
of lactating rats. It is not known whether saxagliptin or metformin are
secreted in human milk. Because many drugs are secreted in human milk, caution
should be exercised when KOMBIGLYZE XR is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of KOMBIGLYZE XR in pediatric
patients under 18 years of age have not been established. Additionally, studies
characterizing the pharmacokinetics of KOMBIGLYZE XR in pediatric patients have
not been performed.
Geriatric Use
KOMBIGLYZE XR
Elderly patients are more likely to have decreased renal
function. Because metformin is contraindicated in patients with renal
impairment, carefully monitor renal function in the elderly and use KOMBIGLYZE
XR with caution as age increases.
Saxagliptin
In the six, double-blind, controlled clinical safety and
efficacy trials of saxagliptin, 634 (15.3%) of the 4148 randomized patients
were 65 years and over, and 59 (1.4%) patients were 75 years and over. No
overall differences in safety or effectiveness were observed between patients
≥ 65 years old and the younger patients. 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.
Metformin Hydrochloride
Controlled clinical studies of metformin did not include
sufficient numbers of elderly patients to determine whether they respond
differently from younger patients, although other reported clinical experience
has not identified differences in responses between the elderly and young
patients. Metformin is known to be substantially excreted by the kidney.
Because the risk of lactic acidosis with metformin is greater in patients with impaired renal function, KOMBIGLYZE XR should
only be used in patients with normal renal function. The initial and
maintenance dosing of metformin should be conservative in patients with
advanced age due to the potential for decreased renal function in this
population. Any dose adjustment should be based on a careful assessment of
renal function.
Dosage (Posology) and method of administration
Recommended Dosage
The dosage of KOMBIGLYZE XR
should be individualized on the basis of the patient's current regimen,
effectiveness, and tolerability. KOMBIGLYZE XR should generally be administered
once daily with the evening meal, with gradual dose titration to reduce the
gastrointestinal side effects associated with metformin. The following dosage
forms are available:
- KOMBIGLYZE XR (saxagliptin and
metformin HCl extended-release) tablets 5 mg/500 mg
- KOMBIGLYZE XR (saxagliptin and
metformin HCl extended-release) tablets 5 mg/1000 mg
- KOMBIGLYZE XR (saxagliptin and
metformin HCl extended-release) tablets 2.5 mg/1000 mg
The recommended starting dose
of KOMBIGLYZE XR in patients who need 5 mg of saxagliptin and who are not
currently treated with metformin is 5 mg saxagliptin/ 500 mg metformin
extended-release once daily with gradual dose escalation to reduce the
gastrointestinal side effects due to metformin.
In patients treated with
metformin, the dosage of KOMBIGLYZE XR should provide metformin at the dose
already being taken, or the nearest therapeutically appropriate dose. Following
a switch from metformin immediate-release to metformin extended-release,
glycemic control should be closely monitored and dosage adjustments made
accordingly.
Patients who need 2.5 mg
saxagliptin in combination with metformin extended-release may be treated with
KOMBIGLYZE XR 2.5 mg/1000 mg. Patients who need 2.5 mg saxagliptin who are
either metformin naive or who require a dose of metformin higher than 1000 mg
should use the individual components.
The maximum daily recommended
dosage is 5 mg for saxagliptin and 2000 mg for metformin extended-release.
No studies have been performed
specifically examining the safety and efficacy of KOMBIGLYZE XR in patients
previously treated with other antihyperglycemic medications and switched to
KOMBIGLYZE XR. Any change in therapy of type 2 diabetes should be undertaken
with care and appropriate monitoring as changes in glycemic control can occur.
Inform patients that KOMBIGLYZE
XR tablets must be swallowed whole and never crushed, cut, or chewed.
Occasionally, the inactive ingredients of KOMBIGLYZE XR will be eliminated in
the feces as a soft, hydrated mass that may resemble the original tablet
Dosage Adjustments With Concomitant
Use Of Strong CYP3A4/5 Inhibitors
The maximum recommended dosage
of saxagliptin 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). For these patients, limit the KOMBIGLYZE XR
dosage to 2.5 mg/1000 mg once daily.
Concomitant Use With An Insulin
Secretagogue (e.g., Sulfonylurea) Or With Insulin
When KOMBIGLYZE XR is used in
combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin,
a lower dosage of the insulin secretagogue or insulin may be required to
minimize the risk of hypoglycemia.
Interaction with other medicinal products and other forms of interaction
SIDE EFFECTS
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 with
Monotherapy and with Add-On Combination Therapy
Metformin Hydrochloride
In placebo-controlled
monotherapy trials of metformin extended-release, diarrhea and nausea/vomiting
were reported in > 5% of metformin-treated patients and more commonly than in
placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5%
for nausea/vomiting). Diarrhea led to discontinuation of study medication in
0.6% of the patients treated with metformin extended-release.
Saxagliptin
In two placebo-controlled
monotherapy trials of 24-week duration, patients were treated with saxagliptin
2.5 mg daily, saxagliptin 5 mg daily, and placebo. Three 24-week,
placebo-controlled, add-on combination therapy trials were also conducted: one
with metformin immediate-release, one with a thiazolidinedione (pioglitazone or
rosiglitazone), and one with glyburide. In these three trials, patients were
randomized to add-on therapy with saxagliptin 2.5 mg daily, saxagliptin 5 mg
daily, or placebo.
A saxagliptin 10 mg treatment
arm was included in one of the monotherapy trials and in the add-on combination
trial with metformin immediate-release. The 10 mg saxagliptin dosage is not an
approved dosage.
In a pre-specified pooled
analysis of the 24-week data (regardless of glycemic rescue) from the two
monotherapy trials, the add-on to metformin immediate-release trial, the add-on
to thiazolidinedione (TZD) trial, and the add-on to glyburide trial, the
overall incidence of adverse events in patients treated with saxagliptin 2.5 mg
and saxagliptin 5 mg was similar to placebo (72% and 72.2% versus 70.6%,
respectively). Discontinuation of therapy due to adverse events occurred in 2.2%,
3.3%, and 1.8% of patients receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and
placebo, respectively. The most common adverse events (reported in at least 2
patients treated with saxagliptin 2.5 mg or at least 2 patients treated with
saxagliptin 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%). The adverse reactions in
this pooled analysis reported (regardless of investigator assessment of
causality) in ≥ 5% of patients treated with saxagliptin 5 mg, and more
commonly than in patients treated with placebo are shown in Table 1.
Table 1: Adverse Reactions
in Placebo-Controlled Trials* Reported in ≥ 5% of Patients Treated with
Saxagliptin 5 mg and More Commonly than in Patients Treated with Placebo
| |
Number (%) of Patients |
Saxagliptin 5 mg
N=882 |
Placebo
N=799 |
| Upper respiratory tract infection |
68 (7.7) |
61 (7.6) |
| Urinary tract infection |
60 (6.8) |
49 (6.1) |
| Headache |
57 (6.5) |
47 (5.9) |
| * 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. |
In patients treated with
saxagliptin 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 this pooled analysis,
adverse reactions that were reported in ≥ 2% of patients treated with
saxagliptin 2.5 mg or saxagliptin 5 mg and ≥ 1% more frequently compared
to placebo included: sinusitis (2.9% and 2.6% versus 1.6%, respectively),
abdominal pain (2.4% and 1.7% versus 0.5%), gastroenteritis (1.9% and 2.3%
versus 0.9%), and vomiting (2.2% and 2.3% versus 1.3%).
The incidence rate of fractures
was 1.0 and 0.6 per 100 patient-years, respectively, for saxagliptin (pooled
analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The 10 mg saxagliptin dosage
is not an approved dosage. The incidence rate of fracture events in patients
who received saxagliptin did not increase over time. Causality has not been
established and nonclinical studies have not demonstrated adverse effects of
saxagliptin 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 saxagliptin
is not known.
Adverse Reactions with
Concomitant Use with Insulin
In the add-on to insulin trial
, the incidence of adverse events, including
serious adverse events and discontinuations due to adverse events, was similar
between saxagliptin and placebo, except for confirmed hypoglycemia.
Adverse Reactions Associated
with Saxagliptin Coadministered with Metformin Immediate-Release in
Treatment-Naive Patients with Type 2 Diabetes
Table 2 shows the adverse
reactions reported (regardless of investigator assessment of causality) in
≥ 5% of patients participating in an additional 24-week, active-controlled
trial of coadministered saxagliptin and metformin in treatment-naive patients.
Table 2: Coadministration of
Saxagliptin and Metformin Immediate-Release in Treatment-Naive Patients:
Adverse Reactions Reported in ≥ 5% of Patients Treated with Combination
Therapy of Saxagliptin 5 mg Plus Metformin Immediate-Release (and More Commonly
than in Patients Treated with Metformin Immediate-Release Alone)
| |
Number(%) of Patients |
Saxagliptin 5 mg + Metformin*
N=320 |
Placebo + Metformin*
N=328 |
| Headache |
24 (7.5) |
17 (5.2) |
| Nasopharyngitis |
22 (6.9) |
13 (4.0) |
| * Metformin immediate-release
was initiated at a starting dose of 500 mg daily and titrated up to a maximum
of 2000 mg daily. |
In patients treated with the
combination of saxagliptin and metformin immediate-release, either as
saxagliptin add-on to metformin immediate-release therapy or as
coadministration in treatment-naive patients, diarrhea was the only
gastrointestinal-related event that occurred with an incidence ≥ 5% in any
treatment group in both studies. In the saxagliptin add-on to metformin
immediate-release trial, the incidence of diarrhea was 9.9%, 5.8%, and 11.2% in
the saxagliptin 2.5 mg, 5 mg, and placebo groups, respectively. When
saxagliptin and metformin immediate-release were coadministered in treatment-naive
patients, the incidence of diarrhea was 6.9% in the saxagliptin 5 mg +
metformin immediate-release group and 7.3% in the placebo + metformin
immediate-release group.
Hypoglycemia
In the saxagliptin clinical
trials, 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.
The incidence of reported
hypoglycemia for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo given
as monotherapy was 4% and 5.6% versus 4.1%, respectively. In the add-on to
metformin immediate-release trial, the incidence of reported hypoglycemia was
7.8% with saxagliptin 2.5 mg, 5.8% with saxagliptin 5 mg, and 5% with placebo.
When saxagliptin and metformin immediate-release were coadministered in
treatment-naive patients, the incidence of reported hypoglycemia was 3.4% in
patients given saxagliptin 5 mg + metformin immediate-release and 4% in
patients given placebo + metformin immediate-release.
In the active-controlled trial
comparing add-on therapy with saxagliptin 5 mg to glipizide in patients
inadequately controlled on metformin alone, the incidence of reported hypoglycemia
was 3% (19 events in 13 patients) with saxagliptin 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 saxagliptin-treated patients and in 35 glipizide-treated patients (8.1%)
(p < 0.0001).
In the saxagliptin add-on to
insulin trial, the overall incidence of reported hypoglycemia was 18.4% for
saxagliptin 5 mg and 19.9% for placebo. However, the incidence of confirmed
symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤ 50
mg/dL) was higher with saxagliptin 5 mg (5.3%) versus placebo (3.3%). Among the
patients using insulin in combination with metformin, the incidence of
confirmed symptomatic hypoglycemia was 4.8% with saxagliptin versus 1.9% with
placebo.
In the saxagliptin add-on to
metformin plus sulfonylurea trial, the overall incidence of reported
hypoglycemia was 10.1% for saxagliptin 5 mg and 6.3% for placebo. Confirmed
hypoglycemia was reported in 1.6% of the saxagliptin-treated patients and in
none of the placebo-treated patients.
Hypersensitivity Reactions
Saxagliptin
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
saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. None of these
events in patients who received saxagliptin required hospitalization or were
reported as life-threatening by the investigators. One saxagliptin-treated
patient in this pooled analysis discontinued due to generalized urticaria and
facial edema.
Infections
Saxagliptin
In the unblinded, controlled,
clinical trial database for saxagliptin to date, there have been 6 (0.12%)
reports of tuberculosis among the 4959 saxagliptin-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 the
United States or in Western Europe. One case occurred in Canada in a patient
originally from Indonesia who had recently visited Indonesia. The duration of
treatment with saxagliptin 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
saxagliptin that remained stable throughout saxagliptin 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 saxagliptin use. Causality has not been
established and there are too few cases to date to determine whether
tuberculosis is related to saxagliptin use.
There has been one case of a
potential opportunistic infection in the unblinded, controlled clinical trial
database to date in a saxagliptin-treated patient who developed suspected
foodborne fatal salmonella sepsis after approximately 600 days of saxagliptin
therapy. There have been no spontaneous reports of opportunistic infections
associated with saxagliptin use.
Vital Signs
Saxagliptin
No clinically meaningful changes in vital signs have been
observed in patients treated with saxagliptin alone or in combination with
metformin.
Laboratory Tests
Absolute Lymphocyte Counts
Saxagliptin
There was a dose-related mean decrease in absolute
lymphocyte count observed with saxagliptin. From a baseline mean absolute
lymphocyte count of approximately 2200 cells/microL, mean decreases of
approximately 100 and 120 cells/microL with saxagliptin 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 saxagliptin 5 mg and metformin were coadministered in
treatment-naive patients compared to placebo and metformin. There was no
difference observed for saxagliptin 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 saxagliptin 2.5 mg, 5 mg, 10
mg, and placebo groups, respectively. In most patients, recurrence was not
observed with repeated exposure to saxagliptin although some patients had
recurrent decreases upon rechallenge that led to discontinuation of
saxagliptin. The decreases in lymphocyte count were not associated with
clinically relevant adverse reactions. The 10 mg saxagliptin dosage is not an
approved dosage.
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 saxagliptin on lymphocyte counts in patients with
lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.
Vitamin B12 Concentrations
Metformin Hydrochloride
Metformin may lower serum vitamin B12 concentrations.
Measurement of hematologic parameters on an annual basis is advised in patients
on KOMBIGLYZE XR and any apparent abnormalities should be appropriately
investigated and managed.
Postmarketing Experience
Additional adverse reactions have been identified during
postapproval use of saxagliptin. 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.
- Acute pancreatitis.
- Severe and disabling arthralgia.
DRUG INTERACTIONS
Strong Inhibitors Of CYP3A4/5 Enzymes
Saxagliptin
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 saxagliptin should be limited to
2.5 mg when coadministered with a strong CYP3A4/5 inhibitor.
Cationic Drugs
Metformin Hydrochloride
Cationic drugs (e.g., amiloride, digoxin, morphine,
procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or
vancomycin) that are eliminated by renal tubular secretion theoretically have
the potential for interaction with metformin by competing for common renal
tubular transport systems. Such interaction between metformin and oral
cimetidine has been observed in healthy volunteers. Although such interactions
remain theoretical (except for cimetidine), careful patient monitoring and dose
adjustment of KOMBIGLYZE XR and/or the interfering drug is recommended in
patients who are taking cationic medications that are excreted via the proximal
renal tubular secretory system.
Use With Other Drugs
Metformin Hydrochloride
Some medications can predispose to hyperglycemia and may
lead to loss of glycemic control. These medications include the thiazides and
other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens,
oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium
channel blockers, and isoniazid. When such drugs are administered to a patient
receiving KOMBIGLYZE XR, the patient should be closely observed for loss of
glycemic control. When such drugs are withdrawn from a patient receiving
KOMBIGLYZE XR, the patient should be observed closely for hypoglycemia.
