Overdose
Rosiglitazone
Limited data are available with
regard to overdosage in humans. In clinical trials in volunteers, rosiglitazone
has been administered at single oral doses of up to 20 mg and was well
tolerated. In the event of an overdose, appropriate supportive treatment should
be initiated as dictated by the patient's clinical status.
Glimepiride
An overdosage of glimepiride, as with
other sulfonylureas, can produce severe hypoglycemia. Mild episodes of
hypoglycemia can be treated with oral glucose. Severe hypoglycemic reactions
constitute medical emergencies requiring immediate treatment. Severe
hypoglycemia with coma, seizure, or neurological impairment can be treated with
glucagon or intravenous glucose. Continued observation and additional
carbohydrate intake may be necessary because hypoglycemia may recur after
apparent clinical recovery.
Contraindications
Initiation of AVANDARYL in patients with established New
York Heart Association (NYHA) Class III or IV heart failure is contraindicated.
AVANDARYL is contraindicated in patients with a history
of a hypersensitivity reaction to rosiglitazone or glimepiride or any of the
product's ingredients.
Patients who have developed an allergic reaction to
sulfonamide derivatives may develop an allergic reaction to AVANDARYL. Do not
use AVANDARYL in patients who have a history of an allergic reaction to
sulfonamide derivatives. Reported hypersensitivity reactions include cutaneous
eruptions with or without pruritis as well as more serious reactions (e.g.,
anaphylaxis, angioedema, Stevens-Johnson syndrome, dyspnea).
Undesirable effects
The following adverse reactions are discussed in more
detail elsewhere in the labeling:
- Cardiac Failure With Rosiglitazone
- Major Adverse Cardiovascular Events
- Hypoglycemia
- Edema
- Weight Gain
- Hepatic Effects
- Macular Edema
- Fractures
- Hypersensitivity Reactions
- Hematologic Effects
- Hemolytic Anemia
- Increased Risk of Cardiovascular Mortality for
Sulfonylurea Drugs
- Ovulation
Clinical Trial 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 with rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
Patients With Inadequate Glycemic Control On Diet and
Exercise
Table 3 summarizes adverse events occurring at a
frequency of ≥ 5% in any treatment group in the 28-week, double-blind
trial of AVANDARYL in patients with type 2 diabetes mellitus inadequately
controlled on diet and exercise. Patients in this trial were started on
AVANDARYL 4 mg/1 mg, rosiglitazone 4 mg, or glimepiride 1 mg. Doses could be
increased at 4-week intervals to reach a maximum total daily dose of either 4
mg/4 mg or 8 mg/4 mg for AVANDARYL, 8 mg for rosiglitazone monotherapy, or 4 mg
for glimepiride monotherapy.
Table 3: Adverse Events ( ≥ 5% in any
Treatment Group) Reported by Patients With Inadequate Glycemic Control on Diet
and Exercise in a 28-Week, Double-blind Clinical Trial of AVANDARYL
| Preferred Term |
Glimepiride Monotherapy
N = 222
% |
Rosiglitazone Monotherapy
N = 230
% |
AVANDARYL 4 mg/4 mg
N = 224
% |
AVANDARYL 8 mg/4 mg
N = 218
% |
| Headache |
2.3 |
6.1 |
3.1 |
6.0 |
| Nasopharyngitis |
3.6 |
5.2 |
4.0 |
4.6 |
| Hypertension |
3.6 |
5.2 |
3.1 |
2.3 |
| Hypoglycemiaa |
4.1 |
0.4 |
3.6 |
5.5 |
| a As documented by symptoms and a fingerstick
blood glucose measurement of < 50 mg/dL. |
Hypoglycemia was reported to be generally mild to
moderate in intensity and none of the reported events of hypoglycemia resulted
in withdrawal from the trial. Hypoglycemia requiring parenteral treatment
(i.e., intravenous glucose or glucagon injection) was observed in 3 (0.7%)
patients treated with AVANDARYL.
Edema was reported by 3.2% of patients on AVANDARYL, 3.0%
on rosiglitazone alone, and 2.3% on glimepiride alone.
Congestive heart failure was observed in 1 (0.2%) patient
treated with AVANDARYL and in 1 (0.4%) patient treated with rosiglitazone monotherapy.
Patients Treated With Rosiglitazone Added To Sulfonylurea
Monotherapy And Other Experience With Rosiglitazone Or Glimepiride
Trials utilizing rosiglitazone in combination with a
sulfonylurea provide support for the use of AVANDARYL. Adverse event data from
these trials, in addition to adverse events reported with the use of
rosiglitazone and glimepiride therapy, are presented below.
Rosiglitazone: The most common adverse experiences
with rosiglitazone monotherapy ( ≥ 5%) were upper respiratory tract
infection, injury, and headache. Overall, the types of adverse experiences
reported when rosiglitazone was added to a sulfonylurea were similar to those during
monotherapy with rosiglitazone. In controlled combination therapy trials with
sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be
dose-related, were reported. Few patients were withdrawn for hypoglycemia
( < 1%) and few episodes of hypoglycemia were considered to be severe
( < 1%).
Events of anemia and edema tended to be reported more
frequently at higher doses, and were generally mild to moderate in severity and
usually did not require discontinuation of treatment with rosiglitazone.
Edema was reported by 4.8% of patients receiving
rosiglitazone compared with 1.3% on placebo, and 1.0% on sulfonylurea
monotherapy. The reporting rate of edema was higher for rosiglitazone 8 mg
added to a sulfonylurea (12.4%) compared with other combinations, with the
exception of insulin. Anemia was reported by 1.9% of patients receiving
rosiglitazone compared with 0.7% on placebo, 0.6% on sulfonylurea monotherapy,
and 2.3% on rosiglitazone in combination with a sulfonylurea. Overall, the
types of adverse experiences reported when rosiglitazone was added to a
sulfonylurea were similar to those during monotherapy with rosiglitazone.
In 26-week, double-blind, fixed-dose trials, edema was
reported with higher frequency in the rosiglitazone plus insulin combination
trials (insulin, 5.4%; and rosiglitazone in combination with insulin, 14.7%).
Reports of new onset or exacerbation of congestive heart failure occurred at
rates of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in
combination with rosiglitazone.
Long-term Trial of Rosiglitazone as Monotherapy: A
4- to 6-year trial (ADOPT) compared the use of rosiglitazone (n = 1,456),
glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients
recently diagnosed with type 2 diabetes who were not previously treated with
antidiabetic medication. Table 4 presents adverse reactions without regard to
causality; rates are expressed per 100 patient-years (PY) exposure to account
for the differences in exposure to trial medication across the 3 treatment
groups.
In ADOPT, fractures were reported in a greater number of
women treated with rosiglitazone (9.3%, 2.7/100 patient-years) compared with
glyburide (3.5%, 1.3/100 patient-years) or metformin (5.1%, 1.5/100
patient-years). The majority of the fractures in the women who received
rosiglitazone were reported in the upper arm, hand, and foot. The observed
incidence of fractures for male patients was similar among the 3 treatment
groups.
Table 4: On-therapy Adverse Events [ ≥ 5
Events/100 Patient-Years (PY)] in any Treatment Group Reported in a 4- to
6-Year Clinical Trial of Rosiglitazone as Monotherapy (ADOPT)
| Preferred Term |
Rosiglitazone
N = 1,456
PY = 4,954 |
Glyburide
N = 1,441
PY = 4,244 |
Metformin
N = 1,454
PY = 4,906 |
| Nasopharyngitis |
6.3 |
6.9 |
6.6 |
| Back pain |
5.1 |
4.9 |
5.3 |
| Arthralgia |
5.0 |
4.8 |
4.2 |
| Hypertension |
4.4 |
6.0 |
6.1 |
| Upper respiratory tract infection |
4.3 |
5.0 |
4.7 |
| Hypoglycemia |
2.9 |
13.0 |
3.4 |
| Diarrhea |
2.5 |
3.2 |
6.8 |
Long-term Trial of Rosiglitazone as Combination Therapy (RECORD): RECORD (Rosiglitazone
Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) was a
multicenter, randomized, open-label, non-inferiority trial in subjects with
type 2 diabetes inadequately controlled on maximum doses of metformin or
sulfonylurea (glyburide, gliclazide, or glimepiride) to compare the time to
reach the combined cardiovascular endpoint of cardiovascular death or
cardiovascular hospitalization between patients randomized to the addition of
rosiglitazone versus metformin or sulfonylurea. The trial included patients who
have failed metformin or sulfonylurea monotherapy; those who failed metformin
(n = 2,222) were randomized to receive either add-on rosiglitazone (n = 1,117)
or add-on sulfonylurea (n = 1,105), and those who failed sulfonylurea (n =
2,225) were randomized to receive either add-on rosiglitazone (n = 1,103) or
add-on metformin (n = 1,122). Patients were treated to target HbA1c ≤ 7%
throughout the trial.
The mean age of patients in this trial was 58 years, 52%
were male, and the mean duration of follow-up was 5.5 years. Rosiglitazone
demonstrated non-inferiority to active control for the primary endpoint of
cardiovascular hospitalization or cardiovascular death (HR 0.99, 95% CI:
0.85-1.16). There were no significant differences between groups for secondary
endpoints with the exception of congestive heart failure (see Table 5). The
incidence of congestive heart failure was significantly greater among patients
randomized to rosiglitazone.
Table 5: Cardiovascular (CV) Outcomes for the RECORD
Trial
| Primary Endpoint |
Rosiglitazone
N = 2,220 |
Active Control
N = 2,227 |
Hazard Ratio |
95% CI |
| CV death or CV hospitalization |
321 |
323 |
0.99 |
0.85-1.16 |
| Secondary Endpoint |
| All-cause death |
136 |
157 |
0.86 |
0.68-1.08 |
| CV death |
60 |
71 |
0.84 |
0.59-1.18 |
| Myocardial infarction |
64 |
56 |
1.14 |
0.80-1.63 |
| Stroke |
46 |
63 |
0.72 |
0.49-1.06 |
| CV death, myocardial infarction, or stroke |
154 |
165 |
0.93 |
0.74-1.15 |
| Heart failure |
61 |
29 |
2.10 |
1.35-3.27 |
There was an increased incidence of bone fracture for
subjects randomized to rosiglitazone in addition to metformin or sulfonylurea
compared with those randomized to metformin plus sulfonylurea (8.3% versus
5.3%).
The majority of fractures were reported in the upper limbs and distal lower
limbs. The risk of fracture appeared to be higher in females relative to
control (11.5% versus 6.3%), than in males relative to control (5.3% versus
4.3%). Additional data are necessary to determine whether there is an increased
risk of fracture in males after a longer period of follow-up.
Glimepiride: Approximately 2,800 patients with
type 2 diabetes have been treated with glimepiride in the controlled clinical
trials. In these trials, approximately 1,700 patients were treated with
glimepiride for at least 1 year.
Table 6 summarizes adverse events, other than
hypoglycemia, that were reported in 11 pooled placebo-controlled trials,
whether or not considered to be possibly or probably related to study
medication. Treatment duration ranged from 13 weeks to 12 months. Terms that
are reported represent those that occurred at an incidence of ≥ 5% among
glimepiride-treated patients and more commonly than in patients who received
placebo.
Table 6: Eleven Pooled Placebo-Controlled Trials
Ranging From 13 Weeks to 12 Months: Adverse Events (Excluding Hypoglycemia)
Occurring in ≥ 5% of Glimepiride-Treated Patients and at a Greater
Incidence Than With Placeboa
| Preferred Term |
Glimepiride
N = 745 % |
Placebo
N = 294 % |
| Headache |
8.2 |
7.8 |
| Accidental injuryb |
5.8 |
3.4 |
| Flu syndrome |
5.4 |
4.4 |
| Nausea |
5.0 |
3.4 |
| Dizziness |
5.0 |
2.4 |
a Glimepiride doses ranges from 1 to 16 mg
administered daily.
b Insufficient information to determine whether any of the
accidental injury events were associated with hypoglycemia. |
Hypoglycemia: In a randomized, double-blind,
placebo-controlled monotherapy trial of 14 weeks duration, patients already on
sulfonylurea therapy underwent a 3-week washout period then were randomized to
glimepiride 1 mg, 4 mg, 8 mg or placebo. Patients randomized to glimepiride 4 mg
or 8 mg underwent forced-titration from an initial dose of 1 mg to these final
doses, as tolerated. The overall incidence of possible hypoglycemia (defined by
the presence of at least one symptom that the investigator believed might be
related to hypoglycemia; a concurrent glucose measurement was not required) was
4% for glimepiride 1 mg, 17% for glimepiride 4 mg, 16% for glimepiride 8 mg,
and 0% for placebo. All of these events were self-treated.
In a randomized, double-blind, placebo-controlled
monotherapy trial of 22 weeks duration, patients received a starting dose of
either 1 mg glimepiride or placebo daily. The dose of glimepiride was titrated
to a target fasting plasma glucose of 90 to 150 mg/dL. Final daily doses of
glimepiride were 1, 2, 3, 4, 6, or 8 mg. The overall incidence of possible
hypoglycemia (as defined above for the 14-week trial) for glimepiride versus
placebo was 19.7% versus 3.2%. All of these events were self-treated.
Weight Gain: Glimepiride, like all sulfonylureas,
can cause weight gain.
Allergic Reactions: In clinical trials, allergic
reactions, such as pruritus, erythema, urticaria, and morbilliform or
maculopapular eruptions, occurred in less than 1% of glimepiride-treated
patients. These may resolve despite continued treatment with glimepiride. There
are postmarketing reports of more serious allergic reactions (e.g., dyspnea,
hypotension, shock).
Laboratory Abnormalities
Rosiglitazone
Hematologic: Decreases in mean hemoglobin and
hematocrit occurred in a dose-related fashion in adult patients treated with
rosiglitazone (mean decreases in individual trials as much as 1.0 g/dL
hemoglobin and as much as 3.3% hematocrit). The changes occurred primarily during
the first 3 months following initiation of therapy with rosiglitazone or
following a dose increase in rosiglitazone. The time course and magnitude of
decreases were similar in patients treated with a combination of rosiglitazone
and other hypoglycemic agents or monotherapy with rosiglitazone. White blood
cell counts also decreased slightly in adult patients treated with
rosiglitazone. Decreases in hematologic parameters may be related to increased
plasma volume observed with treatment with rosiglitazone.
Lipids: Changes in serum lipids have been observed
following treatment with rosiglitazone in adults.
Serum Transaminase Levels: In pre-approval
clinical trials in 4,598 patients treated with rosiglitazone encompassing
approximately 3,600 patient-years of exposure, there was no evidence of
drug-induced hepatotoxicity.
In pre-approval controlled trials, 0.2% of patients
treated with rosiglitazone had reversible elevations in ALT > 3X the upper
limit of normal compared with 0.2% on placebo and 0.5% on active comparators.
The ALT elevations in patients treated with rosiglitazone were reversible.
Hyperbilirubinemia was found in 0.3% of patients treated with rosiglitazone
compared with 0.9% treated with placebo and 1% in patients treated with active
comparators. In pre-approval clinical trials, there were no cases of
idiosyncratic drug reactions leading to hepatic failure.
In the 4- to 6-year ADOPT trial, patients treated with
rosiglitazone (4,954 patient-years exposure), glyburide (4,244 patient-years
exposure), or metformin (4,906 patient-years exposure) as monotherapy had the
same rate of ALT increase to > 3X upper limit of normal (0.3 per 100
patient-years exposure).
In the RECORD trial, patients randomized to rosiglitazone
in addition to metformin or sulfonylurea (10,849 patient-years exposure) and to
metformin plus sulfonylurea (10,209 patient-years exposure) had a rate of ALT
increase to ≥ 3X upper limit of normal of approximately 0.2 and 0.3 per
100 patient-years exposure, respectively.
Glimepiride: Serum Transaminase Levels: In 11
pooled, placebo-controlled trials of glimepiride, 1.9% of glimepiride-treated
patients and 0.8% of placebo-treated patients developed serum ALT > 2X the
upper limit of the reference range.
Postmarketing Experience
In addition to adverse reactions reported from clinical
trials, the events described below have been identified during post-approval
use of AVANDARYL or its individual components. Because these events are
reported voluntarily from a population of unknown size, it is not possible to
reliably estimate their frequency or to always establish a causal relationship
to drug exposure.
Rosiglitazone: In patients receiving thiazolidinedione therapy, serious
adverse events with or without a fatal outcome, potentially related to volume
expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions)
have been reported.
There are postmarketing reports with rosiglitazone of
hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of
normal, and hepatic failure with and without fatal outcome, although causality
has not been established.
There are postmarketing reports with rosiglitazone of
rash, pruritus, urticaria, angioedema, anaphylactic reaction, Stevens-Johnson
syndrome , and new onset or worsening diabetic
macular edema with decreased visual acuity.
Glimepiride
- Serious hypersensitivity reactions, including
anaphylaxis, angioedema, and Stevens-Johnson syndrome
- Hemolytic anemia in patients with and without G6PD
deficiency
- Impairment of liver function (e.g., with cholestasis and
jaundice), as well as hepatitis, which may progress to liver failure
- Porphyria cutanea tarda, photosensitivity reactions, and
allergic vasculitis
- Leukopenia, agranulocytosis, aplastic anemia, and
pancytopenia
- Thrombocytopenia (including severe cases with platelet
count less than 10,000/μL) and thrombocytopenic purpura
- Hepatic porphyria reactions and disulfiram-like reactions
- Hyponatremia and syndrome of inappropriate antidiuretic
hormone secretion (SIADH), most often in patients who are on other medications
or who have medical conditions known to cause hyponatremia or increase release
of antidiuretic hormone
Therapeutic indications
AVANDARYL is indicated as an
adjunct to diet and exercise to improve glycemic control in adults with type 2
diabetes mellitus.
Important Limitations Of Use
- Due to its mechanism of action,
rosiglitazone is active only in the presence of endogenous insulin. Therefore,
AVANDARYL should not be used in patients with type 1 diabetes or for the
treatment of diabetic ketoacidosis.
- Coadministration of AVANDARYL
with insulin is not recommended.
Pharmacodynamic properties
The lipid profiles of rosiglitazone and glimepiride in a
clinical trial of patients with inadequate glycemic control on diet and
exercise were consistent with the known profile of each monotherapy. AVANDARYL
was associated with increases in HDL and LDL (3% to 4% for each) and decreases
in triglycerides (-4%), that were not considered to be clinically meaningful.
The pattern of LDL and HDL changes following therapy with
rosiglitazone in patients previously treated with a sulfonylurea was generally
similar to those seen with rosiglitazone in monotherapy. Rosiglitazone as
monotherapy was associated with increases in total cholesterol, LDL, and HDL
and decreases in free fatty acids. The changes in triglycerides during therapy
with rosiglitazone were variable and were generally not statistically different
from placebo or glyburide controls.
Pharmacokinetic properties
In a bioequivalence trial of AVANDARYL 4 mg/4 mg, the
area under the curve (AUC) and maximum concentration (Cmax) of rosiglitazone
following a single dose of the combination tablet were bioequivalent to
rosiglitazone 4 mg concomitantly administered with glimepiride 4 mg under
fasted conditions. The AUC of glimepiride following a single fasted 4 mg/4 mg
dose was equivalent to glimepiride concomitantly administered with
rosiglitazone, while the Cmax was 13% lower when administered as the
combination tablet (see Table 7).
Table 7: Pharmacokinetic Parameters for Rosiglitazone
and Glimepiride (N = 28)
| Parameter (Units) |
Rosiglitazone |
Glimepiride |
| Regimen A |
Regimen B |
Regimen A |
Regimen B |
| AUC 0-inf (ng•h/mL) |
1,259(833-2,060) |
1,253(756-2,758) |
1,052(643-2,117) |
1,101(648-2,555) |
| AUC0-t (ng•h/mL) |
1,231(810-2,019) |
1,224(744-2,654) |
944(511-1,898) |
1,038(606-2,337) |
| Cmax (ng/mL) |
257(157-352) |
251(77.3-434) |
151(63.2-345) |
173(70.5-329) |
| T½(h) |
3.53(2.60-4.57) |
3.54(2.10-5.03) |
7.63(4.42-12.4) |
5.08(1.80-11.31) |
| Tmax(h) |
1.00(0.48-3.02) |
0.98(0.48-5.97) |
3.02(1.50-8.00) |
2.53(1.00-8.03) |
AUC = area under the curve; Cmax = maximum concentration;
T½ = terminal half-life; Tmax = time of maximum concentration.
Regimen A = AVANDARYL 4 mg/4 mg tablet; Regimen B = Concomitant dosing of a
rosiglitazone 4-mg tablet AND a glimepiride 4-mg tablet.
Data presented as geometric mean (range), except T½ which is presented as
arithmetic mean (range) and Tmax, which is presented as median (range). |
The rate and extent of absorption of both the
rosiglitazone component and glimepiride component of AVANDARYL when taken with
food were equivalent to the rate and extent of absorption of rosiglitazone and
glimepiride when administered concomitantly as separate tablets with food.
Absorption
The AUC and Cmax of glimepiride increased in a
dose-proportional manner following administration of AVANDARYL 4 mg/1 mg, 4
mg/2 mg, and 4 mg/4 mg. Administration of AVANDARYL in the fed state resulted
in no change in the overall exposure of rosiglitazone; however, the Cmax of
rosiglitazone decreased by 32% compared with the fasted state. There was an
increase in both AUC (19%) and Cmax (55%) of glimepiride in the fed state
compared with the fasted state.
Rosiglitazone: The absolute bioavailability of
rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after
dosing. The Cmax and AUC of rosiglitazone increase in a dose-proportional
manner over the therapeutic dose range.
Glimepiride: Studies with single oral doses of
glimepiride in healthy subjects and with multiple oral doses in patients with
type 2 diabetes showed peak drug concentrations (Cmax) 2 to 3 hours post-dose.
When glimepiride was given with meals, the mean Cmax and AUC were decreased by
8% and 9%, respectively.
Glimepiride does not accumulate in serum following
multiple dosing. The pharmacokinetics of glimepiride does not differ between
healthy subjects and patients with type 2 diabetes. Clearance of glimepiride
after oral administration does not change over the 1 mg to 8 mg dose range,
indicating linear pharmacokinetics.
In healthy subjects, the intra- and inter-individual
variabilities of glimepiride pharmacokinetic parameters were 15 to 23% and 24
to 29%, respectively.
Distribution
Rosiglitazone: The mean (CV%) oral volume of
distribution (Vss/F) of rosiglitazone is approximately 17.6 (30%) liters, based
on a population pharmacokinetic analysis. Rosiglitazone is approximately 99.8%
bound to plasma proteins, primarily albumin.
Glimepiride: After intravenous (IV) dosing in
healthy subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg), and
the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than
99.5%.
Metabolism And Excretion
Rosiglitazone: Rosiglitazone is extensively
metabolized with no unchanged drug excreted in the urine. The major routes of
metabolism were N-demethylation and hydroxylation, followed by conjugation with
sulfate and glucuronic acid. All the circulating metabolites are considerably
less potent than parent and, therefore, are not expected to contribute to the
insulin-sensitizing activity of rosiglitazone. In vitro data demonstrate that
rosiglitazone is predominantly metabolized by cytochrome P450 (CYP) isoenzyme
2C8, with CYP2C9 contributing as a minor pathway. Following oral or IV
administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the
dose was eliminated in the urine and in the feces, respectively. The plasma
half-life of [14C]related material ranged from 103 to 158 hours. The
elimination half-life is 3 to 4 hours and is independent of dose.
Glimepiride: Glimepiride is completely metabolized
by oxidative biotransformation after either an IV or oral dose. The major
metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl
derivative (M2). Cytochrome P450 2C9 is involved in the biotransformation of
glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic
enzymes. M2 is inactive. In animals, M1 possesses about 1/3 of the
pharmacological activity of glimepiride, but it is unclear whether M1 results
in clinically meaningful effects on blood glucose in humans.
When [14C]glimepiride was given orally to 3
healthy male subjects, approximately 60% of the total radioactivity was
recovered in the urine in 7 days. M1 and M2 accounted for 80% to 90% of the
radioactivity recovered in the urine. The ratio of M1 to M2 in the urine was
approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of
the total radioactivity was recovered in feces and M1 and M2 (predominant)
accounted for about 70% of that recovered in feces. No parent drug was
recovered from urine or feces. After IV dosing in patients, no significant
biliary excretion of glimepiride or its M1 metabolite was observed.
Date of revision of the text
Mar 2015.
Fertility, pregnancy and lactation
Pregnancy Category C
All pregnancies have a background risk of birth defects,
loss, or other adverse outcome regardless of drug exposure. This background
risk is increased in pregnancies complicated by hyperglycemia and may be
decreased with good metabolic control. It is essential for patients with
diabetes or history of gestational diabetes to maintain good metabolic control
before conception and throughout pregnancy. Careful monitoring of glucose
control is essential in such patients. Most experts recommend that insulin
monotherapy be used during pregnancy to maintain blood glucose levels as close
to normal as possible. AVANDARYL should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Human Data
There are no adequate and well-controlled trials with
AVANDARYL or its individual components in pregnant women. Rosiglitazone has
been reported to cross the human placenta and be detectable in fetal tissue.
The clinical significance of these findings is unknown.
Animal Studies
No animal studies have been conducted with AVANDARYL. The
following data are based on findings in studies performed with rosiglitazone or
glimepiride individually.
Rosiglitazone: There was no effect on implantation
or the embryo with rosiglitazone treatment during early pregnancy in rats, but
treatment during mid-late gestation was associated with fetal death and growth
retardation in both rats and rabbits. Teratogenicity was not observed at doses
up to 3 mg/kg in rats and 100 mg/kg in rabbits (approximately 20 and 75 times
human AUC at the maximum recommended human daily dose, respectively).
Rosiglitazone caused placental pathology in rats (3 mg/kg/day). Treatment of
rats during gestation through lactation reduced litter size, neonatal
viability, and postnatal growth, with growth retardation reversible after
puberty. For effects on the placenta, embryo/fetus, and offspring, the
no-effect dose was 0.2 mg/kg/day in rats and 15 mg/kg/day in rabbits. These
no-effect levels are approximately 4 times human AUC at the maximum recommended
human daily dose. Rosiglitazone reduced the number of uterine implantations and
live offspring when juvenile female rats were treated at 40 mg/kg/day from 27
days of age through to sexual maturity (approximately 68 times human AUC at the
maximum recommended daily dose). The no-effect level was 2 mg/kg/day
(approximately 4 times human AUC at the maximum recommended daily dose). There
was no effect on pre- or post-natal survival or growth.
Glimepiride: In animal studies there was no
increase in congenital anomalies, but an increase in fetal deaths occurred in
rats and rabbits at glimepiride doses 50 times (rats) and 0.1 times (rabbits)
the maximum recommended human dose (based on body surface area). This fetotoxicity,
observed only at doses inducing maternal hypoglycemia, is believed to be
directly related to the pharmacologic (hypoglycemic) action of glimepiride and
has been similarly noted with other sulfonylureas.
Nonteratogenic Effects: Prolonged severe
hypoglycemia (4 to 10 days) has been reported in neonates born to mothers
receiving a sulfonylurea at the time of delivery.
Qualitative and quantitative composition
Dosage Forms And Strengths
Each rounded triangular tablet contains rosiglitazone
maleate and glimepiride as follows:
- 4 mg/1 mg - yellow, gsk debossed on one side and 4/1 on
the other.
- 4 mg/2 mg - orange, gsk debossed on one side and 4/2 on
the other.
- 4 mg/4 mg - pink, gsk debossed on one side and 4/4 on the
other.
- 8 mg/2 mg - pale pink, gsk debossed on one side and 8/2
on the other.
- 8 mg/4 mg - red, gsk debossed on one side and 8/4 on the
other.
Storage And Handling
Each rounded triangular tablet contains rosiglitazone as
the maleate and glimepiride as follows:
4 mg/1 mg - yellow, gsk debossed on one side and 4/1 on
the other.
4 mg/2 mg - orange, gsk debossed on one side and 4/2 on
the other.
4 mg/4 mg - pink, gsk debossed on one side and 4/4 on the
other.
8 mg/2 mg - pale pink, gsk debossed on one side and 8/2
on the other.
8 mg/4 mg - red, gsk debossed on one side and 8/4 on the
other.
4 mg/1 mg bottles of 30: NDC 0173-0841-13
4 mg/2 mg bottles of 30: NDC 0173-0842-13
4 mg/4 mg bottles of 30: NDC 0173-0843-13
8 mg/2 mg bottles of 30: NDC 0173-0844-13
8 mg/4 mg bottles of 30: NDC 0173-0845-13
Store at 25°C (77°F); excursions permitted to 15° to 30°C
(59° to 86°F). Dispense in a tight, light-resistant container.
GlaxoSmithKlinem Research Triangle Park, NC 27709. Revised: Mar 2015.
Special warnings and precautions for use
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Cardiac Failure With Rosiglitazone
Rosiglitazone, like other thiazolidinediones, alone or in
combination with other antidiabetic agents, can cause fluid retention, which
may exacerbate or lead to heart failure. Patients should be observed for signs
and symptoms of heart failure. If these signs and symptoms develop, the heart
failure should be managed according to current standards of care. Furthermore,
discontinuation or dose reduction of rosiglitazone must be considered.
Patients with congestive heart failure (CHF) NYHA Class I
and II treated with rosiglitazone have an increased risk of cardiovascular
events. A 52-week, double-blind, placebo-controlled, echocardiographic trial
was conducted in 224 patients with type 2 diabetes mellitus and NYHA Class I or
II CHF (ejection fraction ≤ 45%) on background antidiabetic and CHF
therapy. An independent committee conducted a blinded evaluation of
fluid-related events (including congestive heart failure) and cardiovascular
hospitalizations according to predefined criteria (adjudication). Separate from
the adjudication, other cardiovascular adverse events were reported by
investigators. Although no treatment difference in change from baseline of
ejection fractions was observed, more cardiovascular adverse events were
observed with rosiglitazone treatment compared with placebo during the 52-week
trial. (See Table 1.)
Table 1: Emergent Cardiovascular Adverse Events in
Patients With Congestive Heart Failure (NYHA Class I and II) Treated With
Rosiglitazone or Placebo (in Addition to Background Antidiabetic and CHF
Therapy)
| Events |
Rosiglitazone
N = 110
n (%) |
Placebo
N = 114
n (%) |
| Adjudicated |
| Cardiovascular deaths |
5 (5%) |
4 (4%) |
| CHF worsening |
7 (6%) |
4 (4%) |
| - with overnight hospitalization |
5 (5%) |
4 (4%) |
| - without overnight hospitalization |
2 (2%) |
0 (0%) |
| New or worsening edema |
28 (25%) |
10 (9%) |
| New or worsening dyspnea |
29 (26%) |
19 (17%) |
| Increases in CHF medication |
36 (33%) |
20 (18%) |
| Cardiovascular hospitalizationa |
21 (19%) |
15 (13%) |
| Investigator-reported, non-adjudicated |
| Ischemic adverse events |
10 (9%) |
5 (4%) |
| - Myocardial infarction |
5 (5%) |
2 (2%) |
| - Angina |
6 (5%) |
3 (3%) |
| a Includes hospitalization for any
cardiovascular reason. |
In a long-term, cardiovascular outcome trial (RECORD) in
patients with type 2 diabetes , the incidence of
heart failure was higher in patients treated with rosiglitazone [2.7%
(61/2,220) compared with active control 1.3% (29/2,227), HR 2.10 (95% CI: 1.35,
3.27)].
Initiation of AVANDARYL in patients with established NYHA
Class III or IV heart failure is contraindicated. AVANDARYL is not recommended
in patients with symptomatic heart failure.
Patients experiencing acute coronary syndromes have not
been studied in controlled clinical trials. In view of the potential for
development of heart failure in patients having an acute coronary event,
initiation of AVANDARYL is not recommended for patients experiencing an acute
coronary event, and discontinuation of AVANDARYL during this acute phase should
be considered.
Patients with NYHA Class III and IV cardiac status (with
or without CHF) have not been studied in controlled clinical trials. AVANDARYL
is not recommended in patients with NYHA Class III and IV cardiac status.
Congestive Heart Failure During Coadministration Of Rosiglitazone
With Insulin
In trials in which rosiglitazone was added to insulin,
rosiglitazone increased the risk of congestive heart failure. Coadministration
of rosiglitazone and insulin is not recommended.
In 7 controlled, randomized, double-blind trials which
had durations from 16 to 26 weeks and which were included in a meta-analysis , patients
with type 2 diabetes mellitus were randomized to coadministration of
rosiglitazone and insulin (N = 1,018) or insulin (N = 815). In these 7 trials,
rosiglitazone was added to insulin. These trials included patients with
long-standing diabetes (median duration of 12 years) and a high prevalence of
pre-existing medical conditions, including peripheral neuropathy, retinopathy, ischemic
heart disease, vascular disease, and congestive heart failure. The total number
of patients with emergent congestive heart failure was 23 (2.3%) and 8 (1.0%)
in the rosiglitazone plus insulin and insulin groups, respectively.
Heart Failure In Observational Studies Of Elderly
Diabetic Patients Comparing Rosiglitazone To Pioglitazone
Three observational studies in elderly diabetic patients
(age 65 years and older) found that rosiglitazone statistically significantly
increased the risk of hospitalized heart failure compared to use of
pioglitazone. One other observational study in patients with a mean age of 54
years, which also included an analysis in a subpopulation of patients > 65
years of age, found no statistically significant increase in emergency
department visits or hospitalization for heart failure in patients treated with
rosiglitazone compared to pioglitazone in the older subgroup.
Major Adverse Cardiovascular Events
Data from long-term, prospective, randomized, controlled
clinical trials of rosiglitazone versus metformin or sulfonylureas,
particularly a cardiovascular outcome trial (RECORD), observed no difference in
overall mortality or in major adverse cardiovascular events (MACE) and its
components. A meta-analysis of mostly short-term trials suggested an increased
risk for myocardial infarction with rosiglitazone compared with placebo.
Cardiovascular Events In Large, Long-term, Prospective,
Randomized, Controlled Trials Of Rosiglitazone
RECORD, a prospectively designed cardiovascular outcome
trial (mean follow-up 5.5 years; 4,447 patients), compared the addition of
rosiglitazone to metformin or a sulfonylurea (N = 2,220) with a control group
of metformin plus sulfonylurea (N = 2,227) in patients with type 2 diabetes. Non-inferiority was demonstrated for the primary
endpoint, cardiovascular hospitalization or cardiovascular death, for
rosiglitazone compared with control [HR 0.99 (95% CI: 0.85, 1.16)]
demonstrating no overall increased risk in cardiovascular morbidity or
mortality. The hazard ratios for total mortality and MACE were consistent with
the primary endpoint and the 95% CI similarly excluded a 20% increase in risk
for rosiglitazone. The hazard ratios for the components of MACE were 0.72 (95%
CI: 0.49, 1.06) for stroke, 1.14 (95% CI: 0.80, 1.63) for myocardial
infarction, and 0.84 (95% CI: 0.59, 1.18) for cardiovascular death.
The results of RECORD are consistent with the findings of
2 earlier long-term, prospective, randomized, controlled clinical trials (each
trial > 3 years' duration; total of 9,620 patients) (see Figure 1). In
patients with impaired glucose tolerance (DREAM trial), although the incidence
of cardiovascular events was higher among subjects who were randomized to
rosiglitazone in combination with ramipril than among subjects randomized to
ramipril alone, no statistically significant differences were observed for MACE
and its components between rosiglitazone and placebo. In type 2 diabetes
patients who were initiating oral agent monotherapy (ADOPT trial), no
statistically significant differences were observed for MACE and its components
between rosiglitazone and metformin or a sulfonylurea.
Figure 1: Hazard Ratios for the Risk of MACE,
Myocardial Infarction, and Total Mortality With Rosiglitazone Compared With a
Control Group in Long-term Trials
Cardiovascular Events In A Group
Of 52 Clinical Trials
In a meta-analysis of 52
double-blind, randomized, controlled clinical trials designed to assess
glucose-lowering efficacy in type 2 diabetes (mean duration 6 months), a
statistically significant increased risk of myocardial infarction with
rosiglitazone versus pooled comparators was observed [0.4% versus 0.3%; OR 1.8,
(95% CI: 1.03, 3.25)]. A statistically non-significant increased risk of MACE
was observed with rosiglitazone versus pooled comparators (OR 1.44, 95% CI:
0.95, 2.20). In the placebo-controlled trials, a statistically significant
increased risk of myocardial infarction [0.4% versus 0.2%, OR 2.23 (95% CI:
1.14, 4.64)] and statistically non-significant increased risk of MACE [0.7%
versus 0.5%, OR 1.53 (95% CI: 0.94, 2.54)] with rosiglitazone were observed. In
the active-controlled trials, there was no increased risk of myocardial
infarction or MACE.
Mortality In Observational
Studies Of Rosiglitazone Compared To Pioglitazone
Three observational studies in
elderly diabetic patients (age 65 years and older) found that rosiglitazone
statistically significantly increased the risk of all-cause mortality compared
to use of pioglitazone. One observational study in patients with a mean age of
54 years found no difference in all-cause mortality between patients
treated with rosiglitazone compared to pioglitazone and reported similar
results in the subpopulation of patients > 65 years of age. One additional
small, prospective, observational study found no statistically significant
differences for CV mortality and all-cause mortality in patients treated with
rosiglitazone compared to pioglitazone.
Hypoglycemia
AVANDARYL is a combination tablet containing
rosiglitazone and glimepiride, a sulfonylurea. All sulfonylurea drugs are
capable of producing severe hypoglycemia. Proper patient selection, dosage, and
instructions are important to avoid hypoglycemic episodes. Elderly patients are
particularly susceptible to hypoglycemic action of glucose-lowering drugs.
Debilitated or malnourished patients, and those with adrenal, pituitary, renal,
or hepatic insufficiency are particularly susceptible to the hypoglycemic action
of glucose-lowering drugs. A starting dose of 1 mg glimepiride, as contained in
AVANDARYL 4 mg/1 mg, followed by appropriate dose titration is recommended in
these patients. Hypoglycemia may be
difficult to recognize in the elderly and in people who are taking
beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is
more likely to occur when caloric intake is deficient, after severe or
prolonged exercise, when alcohol is ingested, or when more than one
glucose-lowering drug is used.
Patients receiving rosiglitazone in combination with a
sulfonylurea may be at risk for hypoglycemia, and a reduction in the dose of
the sulfonylurea may be necessary.
Edema
AVANDARYL should be used with caution in patients with
edema. In a clinical trial in healthy volunteers who received 8 mg of
rosiglitazone once daily for 8 weeks, there was a statistically significant
increase in median plasma volume compared with placebo.
Since thiazolidinediones, including rosiglitazone, can
cause fluid retention, which can exacerbate or lead to congestive heart
failure, AVANDARYL should be used with caution in patients at risk for heart
failure. Patients should be monitored for signs and symptoms of heart failure.
In controlled clinical trials of patients with type 2
diabetes, mild to moderate edema was reported in patients treated with
rosiglitazone, and may be dose-related. Patients with ongoing edema were more
likely to have adverse events associated with edema if started on combination
therapy with insulin and rosiglitazone. The use
of AVANDARYL in combination with insulin is not recommended.
Weight Gain
Dose-related weight gain was seen with AVANDARYL,
rosiglitazone alone, and rosiglitazone together with other hypoglycemic agents
(see Table 2). The mechanism of weight gain is unclear but probably involves a
combination of fluid retention and fat accumulation.
Table 2: Weight Changes (kg) From Baseline at Endpoint
During Clinical Trials [Median (25th, 75th Percentiles)]
| Monotherapy |
| Duration |
Contro Group |
Rosiglitazone 4 mg |
Rosiglitazone 8 mg |
| 26 weeks |
Placebo |
-0.9 (-2.8, 0.9) N = 210 |
1.0 (-0.9, 3.6) N = 436 |
3.1 (1.1, 5.8) N = 439 |
| 52 weeks |
Sulfonylurea |
2.0 (0, 4.0) N = 173 |
2.0 (-0.6, 4.0) N = 150 |
2.6 (0, 5.3) N = 157 |
| Combination Therapy |
| Duration |
Contro Group |
Rosiglitazone + Control Therapy |
| Rosiglitazone 4 mg |
Rosiglitazone 8 mg |
| 24-26 weeks |
Sulfonylurea |
0 (-1.0, 1.3) N = 1,155 |
2.2 (0.5, 4.0) N = 613 |
3.5 (1.4, 5.9) N = 841 |
| 26 weeks |
Metformin |
-1.4 (-3.2, 0.2) N = 175 |
0.8 (-1.0, 2.6) N = 100 |
2.1 (0, 4.3) N = 184 |
| 26 weeks |
Insulin |
0.9 (-0.5, 2.7) N = 162 |
4.1 (1.4, 6.3) N = 164 |
5.4 (3.4, 7.3) N = 150 |
| AVANDARYL in Patients With Inadequate Control on Diet and Exercise |
| Duration |
Contro |
Group |
AVANDARYL 4 mg/4 mg |
AVANDARYL 8 mg/4 mg |
| 28 weeks |
Glimepiride |
1.1 (-1.1, 3.2) N = 222 |
2.2 (0, 4.5) N = 221 |
2.9 (0, 5.8) N = 217 |
| Rosiglitazone |
0.9 (-1.4, 3.2) N = 228 |
In a 4- to 6-year, monotherapy, comparative trial (ADOPT)
in patients recently diagnosed with type 2 diabetes not previously treated with
antidiabetic medication, the median weight change (25th, 75th percentiles) from
baseline at 4 years was 3.5 kg (0.0, 8.1) for rosiglitazone, 2.0 kg (-1.0, 4.8)
for glyburide, and -2.4 kg (-5.4, 0.5) for metformin.
In postmarketing experience with rosiglitazone alone or
in combination with other hypoglycemic agents, there have been rare reports of
unusually rapid increases in weight and increases in excess of that generally
observed in clinical trials. Patients who experience such increases should be
assessed for fluid accumulation and volume-related events such as excessive
edema and congestive heart failure.
Hepatic Effects
With sulfonylureas, including glimepiride, there may be
an elevation of liver enzyme levels in rare cases. In isolated instances,
impairment of liver function (e.g., with cholestasis and jaundice), as well as
hepatitis (which may also lead to liver failure) have been reported.
Liver enzymes should be measured prior to the initiation
of therapy with AVANDARYL in all patients and periodically thereafter per the
clinical judgment of the healthcare professional.
Therapy with AVANDARYL should not be initiated in
patients with increased baseline liver enzyme levels (ALT > 2.5X upper limit
of normal). Patients with mildly elevated liver enzymes (ALT levels ≤ 2.5X
upper limit of normal) at baseline or during therapy with AVANDARYL should be
evaluated to determine the cause of the liver enzyme elevation. Initiation of,
or continuation of, therapy with AVANDARYL in patients with mild liver enzyme
elevations should proceed with caution and include close clinical follow-up,
including more frequent liver enzyme monitoring, to determine if the liver
enzyme elevations resolve or worsen. If at any time ALT levels increase to
> 3X the upper limit of normal in patients on therapy with AVANDARYL, liver
enzyme levels should be rechecked as soon as possible. If ALT levels remain
> 3X the upper limit of normal, therapy with AVANDARYL should be
discontinued.
If any patient develops symptoms suggesting hepatic
dysfunction, which may include unexplained nausea, vomiting, abdominal pain,
fatigue, anorexia, and/or dark urine, liver enzymes should be checked. The
decision whether to continue the patient on therapy with AVANDARYL should be
guided by clinical judgment pending laboratory evaluations. If jaundice is
observed, drug therapy should be discontinued.
Macular Edema
Macular edema has been reported in postmarketing
experience in some diabetic patients who were taking rosiglitazone or another
thiazolidinedione. Some patients presented with blurred vision or decreased
visual acuity, but some patients appear to have been diagnosed on routine
ophthalmologic examination. Most patients had peripheral edema at the time
macular edema was diagnosed. Some patients had improvement in their macular
edema after discontinuation of their thiazolidinedione. Patients with diabetes
should have regular eye exams by an ophthalmologist, per the Standards of Care
of the American Diabetes Association. Additionally, any diabetic who reports
any kind of visual symptom should be promptly referred to an ophthalmologist,
regardless of the patient's underlying medications or other physical findings.
Fractures
Long-term trials (ADOPT and RECORD) show an increased
incidence of bone fracture in patients, particularly female patients, taking
rosiglitazone. This increased incidence was
noted after the first year of treatment and persisted during the course of the
trial. The majority of the fractures in the women who received rosiglitazone
occurred in the upper arm, hand, and foot. These sites of fracture are
different from those usually associated with postmenopausal osteoporosis (e.g.,
hip or spine). Other trials suggest that this risk may also apply to men,
although the risk of fracture among women appears higher than that among men.
The risk of fracture should be considered in the care of patients treated with
rosiglitazone, and attention given to assessing and maintaining bone health
according to current standards of care.
Hypersensitivity Reactions
There have been postmarketing reports of hypersensitivity
reactions in patients treated with glimepiride, including serious reactions
such as anaphylaxis, angioedema, and Stevens-Johnson syndrome. If a
hypersensitivity reaction is suspected, promptly discontinue AVANDARYL, assess
for other potential causes for the reaction, and institute alternative
treatment for diabetes.
Hematologic Effects
Decreases in hemoglobin and hematocrit occurred in a
dose-related fashion in adult patients treated with rosiglitazone. The observed changes may be related to the increased
plasma volume observed with treatment with rosiglitazone.
Hemolytic Anemia
Sulfonylureas can cause hemolytic anemia in patients with
glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because glimepiride, a
component of AVANDARYL, is a sulfonylurea, use caution in patients with G6PD
deficiency and consider the use of a non-sulfonylurea alternative. There are
also postmarketing reports of hemolytic anemia in patients receiving
glimepiride who did not have known G6PD deficiency.
Increased Risk Of Cardiovascular Mortality With
Sulfonylureas
The administration of oral hypoglycemic drugs has been
reported to be associated with increased cardiovascular mortality as compared
to treatment with diet alone or diet plus insulin. This warning is based on the
study conducted by the University Group Diabetes Program (UGDP), a long-term,
prospective clinical trial designed to evaluate the effectiveness of
glucose-lowering drugs in preventing or delaying vascular complications in
patients with non-insulin-dependent diabetes. The study involved 823 patients
who were randomly assigned to one of four treatment groups.
UGDP reported that patients treated for 5 to 8 years with
diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of
cardiovascular mortality approximately 2½ times that of patients treated with
diet alone. A significant increase in total mortality was not observed, but the
use of tolbutamide was discontinued based on the increase in cardiovascular
mortality, thus limiting the opportunity for the study to show an increase in
overall mortality. Despite controversy regarding the interpretation of these
results, the findings of the UGDP study provide an adequate basis for this
warning. The patient should be informed of the potential risks and advantages
of glimepiride and of alternative modes of therapy.
Although only one drug in the sulfonylurea class
(tolbutamide) was included in this study, it is prudent from a safety
standpoint to consider that this warning may also apply to other oral
hypoglycemic drugs in this class, in view of their close similarities in mode
of action and chemical structure.
Diabetes And Blood Glucose Control
When a patient stabilized on any antidiabetic regimen is
exposed to stress such as fever, trauma, infection, or surgery, a temporary
loss of glycemic control may occur. At such times, it may be necessary to
withhold AVANDARYL and temporarily administer insulin. AVANDARYL may be
reinstituted after the acute episode is resolved.
Periodic fasting glucose and HbA1c measurements should be
performed to monitor therapeutic response.
Ovulation
Therapy with rosiglitazone, like other
thiazolidinediones, may result in ovulation in some premenopausal anovulatory
women. As a result, these patients may be at an increased risk for pregnancy
while taking rosiglitazone. Thus,
adequate contraception in premenopausal women should be recommended. This
possible effect has not been specifically investigated in clinical trials;
therefore the frequency of this occurrence is not known.
Although hormonal imbalance has been seen in preclinical
studies , the clinical significance of this
finding is not known. If unexpected menstrual dysfunction occurs, the benefits
of continued therapy with AVANDARYL should be reviewed.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
There are multiple medications available to treat type 2
diabetes. The benefits and risks of each available diabetes medication should
be taken into account when choosing a particular diabetes medication for a
given patient.
Patients should be informed of the following:
- AVANDARYL is not recommended in patients with symptomatic
heart failure.
- A meta-analysis of mostly short-term trials suggested an
increased risk for myocardial infarction with rosiglitazone compared with
placebo. Data from long-term clinical trials of rosiglitazone versus other
antidiabetes agents (metformin or sulfonylureas), including a cardiovascular
outcome trial (RECORD), observed no difference in overall mortality or in major
adverse cardiovascular events (MACE) and its components.
- AVANDARYL is not recommended for patients who are taking
insulin.
- Management of type 2 diabetes should include diet
control. Caloric restriction, weight loss, and exercise are essential for the
proper treatment of the diabetic patient because they help improve insulin
sensitivity. This is important not only in the primary treatment of type 2
diabetes, but also in maintaining the efficacy of drug therapy.
- It is important to adhere to dietary instructions and to
regularly have blood glucose and glycosylated hemoglobin (HbA1c) tested. It can
take 2 weeks to see a reduction in blood glucose and 2 to 3 months to see the
full effect of AVANDARYL.
- The risks of hypoglycemia, its symptoms and treatment,
and conditions that predispose to its development should be explained to
patients and their family members.
- Blood will be drawn to check their liver function prior
to the start of therapy and periodically thereafter per the clinical judgment
of the healthcare professional. Patients with unexplained symptoms of nausea,
vomiting, abdominal pain, fatigue, anorexia, or dark urine should immediately
report these symptoms to their physician.
- Patients who experience an unusually rapid increase in
weight or edema or who develop shortness of breath or other symptoms of heart
failure while on AVANDARYL should immediately report these symptoms to their
physician.
- AVANDARYL should be taken with the first meal of the day.
- Therapy with rosiglitazone, like other
thiazolidinediones, may result in ovulation in some premenopausal anovulatory
women. As a result, these patients may be at an increased risk for pregnancy
while taking AVANDARYL. Thus, adequate contraception in premenopausal women
should be recommended. This possible effect has not been specifically
investigated in clinical trials so the frequency of this occurrence is not
known.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No animal studies have been conducted with AVANDARYL. The
following data are based on findings in studies performed with rosiglitazone or
glimepiride alone.
Rosiglitazone: Carcinogenesis: A 2-year
carcinogenicity study was conducted in Charles River CD-1 mice at doses of 0.4,
1.5, and 6 mg/kg/day in the diet (highest dose equivalent to approximately 12
times human AUC at the maximum recommended human daily dose). Sprague-Dawley
rats were dosed for 2 years by oral gavage at doses of 0.05 mg/kg/day, 0.3
mg/kg/day, and 2 mg/kg/day (highest dose equivalent to approximately 10 and 20
times human AUC at the maximum recommended human daily dose for male and female
rats, respectively).
Rosiglitazone was not carcinogenic in the mouse. There
was an increase in incidence of adipose hyperplasia in the mouse at doses
≥ 1.5 mg/kg/day (approximately 2 times human AUC at the maximum
recommended human daily dose). In rats, there was a significant increase in the
incidence of benign adipose tissue tumors (lipomas) at doses ≥ 0.3
mg/kg/day (approximately 2 times human AUC at the maximum recommended human
daily dose). These proliferative changes in both species are considered due to
the persistent pharmacological overstimulation of adipose tissue.
Mutagenesis: Rosiglitazone was not mutagenic or
clastogenic in the in vitro bacterial assays for gene mutation, the in vitro
chromosome aberration test in human lymphocytes, the in vivo mouse micronucleus
test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold)
increase in mutation in the in vitro mouse lymphoma assay in the presence of
metabolic activation.
Impairment Of Fertility: Rosiglitazone had no
effects on mating or fertility of male rats given up to 40 mg/kg/day
(approximately 116 times human AUC at the maximum recommended human daily
dose). Rosiglitazone altered estrous cyclicity (2 mg/kg/day) and reduced
fertility (40 mg/kg/day) of female rats in association with lower plasma levels
of progesterone and estradiol (approximately 20 and 200 times human AUC at the
maximum recommended human daily dose, respectively). No such effects were noted
at 0.2 mg/kg/day (approximately 3 times human AUC at the maximum recommended
human daily dose). In juvenile rats dosed from 27 days of age through to sexual
maturity (at up to 40 mg/kg/day), there was no effect on male reproductive
performance, or on estrous cyclicity, mating performance or pregnancy incidence
in females (approximately 68 times human AUC at the maximum recommended daily
dose). In monkeys, rosiglitazone (0.6 and 4.6 mg/kg/day; approximately 3 and 15
times human AUC at the maximum recommended human daily dose, respectively)
diminished the follicular phase rise in serum estradiol with consequential
reduction in the luteinizing hormone surge, lower luteal phase progesterone
levels, and amenorrhea. The mechanism for these effects appears to be direct inhibition
of ovarian steroidogenesis.
Glimepiride: Carcinogenesis: Studies in rats at
doses of up to 5,000 parts per million (ppm) in complete feed (approximately
340 times the maximum recommended human dose, based on surface area) for 30
months showed no evidence of carcinogenesis. In mice, administration of
glimepiride for 24 months resulted in an increase in benign pancreatic adenoma
formation that was dose-related and was thought to be the result of chronic
pancreatic stimulation. No adenoma formation in mice was observed at a dose of
320 ppm in complete feed, or 46 to 54 mg/kg body weight/day. This is about 35
times the maximum human recommended dose of 8 mg once daily based on surface
area.
Mutagenesis: Glimepiride was non-mutagenic in a
battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell
mutation, chromosomal aberration, unscheduled DNA synthesis, and mouse
micronucleus test).
Impairment of Fertility: There was no effect of
glimepiride on male mouse fertility in animals exposed up to 2,500 mg/kg body
weight ( > 1,700 times the maximum recommended human dose based on surface
area). Glimepiride had no effect on the fertility of male and female rats
administered up to 4,000 mg/kg body weight (approximately 4,000 times the maximum
recommended human dose based on surface area).
Use In Specific Populations
Pregnancy
Pregnancy Category C
All pregnancies have a background risk of birth defects,
loss, or other adverse outcome regardless of drug exposure. This background
risk is increased in pregnancies complicated by hyperglycemia and may be
decreased with good metabolic control. It is essential for patients with
diabetes or history of gestational diabetes to maintain good metabolic control
before conception and throughout pregnancy. Careful monitoring of glucose
control is essential in such patients. Most experts recommend that insulin
monotherapy be used during pregnancy to maintain blood glucose levels as close
to normal as possible. AVANDARYL should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Human Data
There are no adequate and well-controlled trials with
AVANDARYL or its individual components in pregnant women. Rosiglitazone has
been reported to cross the human placenta and be detectable in fetal tissue.
The clinical significance of these findings is unknown.
Animal Studies
No animal studies have been conducted with AVANDARYL. The
following data are based on findings in studies performed with rosiglitazone or
glimepiride individually.
Rosiglitazone: There was no effect on implantation
or the embryo with rosiglitazone treatment during early pregnancy in rats, but
treatment during mid-late gestation was associated w
Dosage (Posology) and method of administration
Therapy with AVANDARYL should
be individualized for each patient. The risk-benefit of initiating monotherapy
versus dual therapy with AVANDARYL should be considered.
No studies have been performed
specifically examining the safety and efficacy of AVANDARYL in patients
previously treated with other oral hypoglycemic agents and switched to
AVANDARYL. Any change in therapy of type 2 diabetes should be undertaken with
care and appropriate monitoring as changes in glycemic control can occur.
Starting Dose
The recommended starting dose
is 4 mg/1 mg administered once daily with the first meal of the day. For adults
already treated with a sulfonylurea or rosiglitazone, a starting dose of 4 mg/2
mg may be considered.
All patients should start the
rosiglitazone component of AVANDARYL at the lowest recommended dose. Further
increases in the dose of rosiglitazone should be accompanied by careful
monitoring for adverse events related to fluid retention.
When switching from combination therapy of rosiglitazone
plus glimepiride as separate tablets, the usual starting dose of AVANDARYL is
the dose of rosiglitazone and glimepiride already being taken.
When colesevelam is coadministered with glimepiride,
maximum plasma concentration and total exposure to glimepiride is reduced.
Therefore, AVANDARYL should be administered at least 4 hours prior to
colesevelam.
Dose Titration
Dose increases should be individualized according to the
glycemic response of the patient. Patients who may be more sensitive to
glimepiride ,
including the elderly, debilitated, or malnourished, and those with renal,
hepatic, or adrenal insufficiency, should be carefully titrated to avoid
hypoglycemia. If hypoglycemia occurs during up-titration of the dose or while
maintained on therapy, a dosage reduction of the glimepiride component of
AVANDARYL may be considered. Increases in the dose of rosiglitazone should be
accompanied by careful monitoring for adverse events related to fluid retention
.
To switch to AVANDARYL for adults currently treated
with rosiglitazone, dose titration of the glimepiride component of
AVANDARYL is recommended if patients are not adequately controlled after 1 to 2
weeks. The glimepiride component may be increased in no more than 2 mg
increments. After an increase in the dosage of the glimepiride component, dose
titration of AVANDARYL is recommended if patients are not adequately controlled
after 1 to 2 weeks.
To switch to AVANDARYL for adults currently treated
with sulfonylurea, it may take 2 weeks to see a reduction in blood glucose
and 2 to 3 months to see the full effect of the rosiglitazone component.
Therefore, dose titration of the rosiglitazone component of AVANDARYL is
recommended if patients are not adequately controlled after 8 to 12 weeks.
Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when
being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to
AVANDARYL due to potential overlapping of drug effect. After an increase in the
dosage of the rosiglitazone component, dose titration of AVANDARYL is
recommended if patients are not adequately controlled after 2 to 3 months.
Maximum Dose
The maximum recommended daily dose is 8 mg rosiglitazone
and 4 mg glimepiride.
Specific Patient Populations
Elderly And Malnourished Patients And Those With Renal,
Hepatic, Or Adrenal Insufficiency
In elderly, debilitated, or malnourished patients, or in
patients with renal, hepatic, or adrenal insufficiency, the starting dose, dose
increments, and maintenance dosage of AVANDARYL should be conservative to avoid
hypoglycemic reactions.
Hepatic Impairment
Liver enzymes should be measured prior to initiating
treatment with AVANDARYL. Therapy with AVANDARYL should not be initiated if the
patient exhibits clinical evidence of active liver disease or increased serum
transaminase levels (ALT > 2.5X upper limit of normal at start of therapy).
After initiation of AVANDARYL, liver enzymes should be monitored periodically
per the clinical judgment of the healthcare professional.
Pregnancy And Lactation
AVANDARYL should not be used during pregnancy or in
nursing mothers.
Pediatric Use
Safety and effectiveness of AVANDARYL in pediatric
patients have not been established. AVANDARYL and its components, rosiglitazone
and glimepiride, are not recommended for use in pediatric patients.
Interaction with other medicinal products and other forms of interaction
SIDE EFFECTS
The following adverse reactions are discussed in more
detail elsewhere in the labeling:
- Cardiac Failure With Rosiglitazone
- Major Adverse Cardiovascular Events
- Hypoglycemia
- Edema
- Weight Gain
- Hepatic Effects
- Macular Edema
- Fractures
- Hypersensitivity Reactions
- Hematologic Effects
- Hemolytic Anemia
- Increased Risk of Cardiovascular Mortality for
Sulfonylurea Drugs
- Ovulation
Clinical Trial 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 with rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
Patients With Inadequate Glycemic Control On Diet and
Exercise
Table 3 summarizes adverse events occurring at a
frequency of ≥ 5% in any treatment group in the 28-week, double-blind
trial of AVANDARYL in patients with type 2 diabetes mellitus inadequately
controlled on diet and exercise. Patients in this trial were started on
AVANDARYL 4 mg/1 mg, rosiglitazone 4 mg, or glimepiride 1 mg. Doses could be
increased at 4-week intervals to reach a maximum total daily dose of either 4
mg/4 mg or 8 mg/4 mg for AVANDARYL, 8 mg for rosiglitazone monotherapy, or 4 mg
for glimepiride monotherapy.
Table 3: Adverse Events ( ≥ 5% in any
Treatment Group) Reported by Patients With Inadequate Glycemic Control on Diet
and Exercise in a 28-Week, Double-blind Clinical Trial of AVANDARYL
| Preferred Term |
Glimepiride Monotherapy
N = 222
% |
Rosiglitazone Monotherapy
N = 230
% |
AVANDARYL 4 mg/4 mg
N = 224
% |
AVANDARYL 8 mg/4 mg
N = 218
% |
| Headache |
2.3 |
6.1 |
3.1 |
6.0 |
| Nasopharyngitis |
3.6 |
5.2 |
4.0 |
4.6 |
| Hypertension |
3.6 |
5.2 |
3.1 |
2.3 |
| Hypoglycemiaa |
4.1 |
0.4 |
3.6 |
5.5 |
| a As documented by symptoms and a fingerstick
blood glucose measurement of < 50 mg/dL. |
Hypoglycemia was reported to be generally mild to
moderate in intensity and none of the reported events of hypoglycemia resulted
in withdrawal from the trial. Hypoglycemia requiring parenteral treatment
(i.e., intravenous glucose or glucagon injection) was observed in 3 (0.7%)
patients treated with AVANDARYL.
Edema was reported by 3.2% of patients on AVANDARYL, 3.0%
on rosiglitazone alone, and 2.3% on glimepiride alone.
Congestive heart failure was observed in 1 (0.2%) patient
treated with AVANDARYL and in 1 (0.4%) patient treated with rosiglitazone monotherapy.
Patients Treated With Rosiglitazone Added To Sulfonylurea
Monotherapy And Other Experience With Rosiglitazone Or Glimepiride
Trials utilizing rosiglitazone in combination with a
sulfonylurea provide support for the use of AVANDARYL. Adverse event data from
these trials, in addition to adverse events reported with the use of
rosiglitazone and glimepiride therapy, are presented below.
Rosiglitazone: The most common adverse experiences
with rosiglitazone monotherapy ( ≥ 5%) were upper respiratory tract
infection, injury, and headache. Overall, the types of adverse experiences
reported when rosiglitazone was added to a sulfonylurea were similar to those during
monotherapy with rosiglitazone. In controlled combination therapy trials with
sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be
dose-related, were reported. Few patients were withdrawn for hypoglycemia
( < 1%) and few episodes of hypoglycemia were considered to be severe
( < 1%).
Events of anemia and edema tended to be reported more
frequently at higher doses, and were generally mild to moderate in severity and
usually did not require discontinuation of treatment with rosiglitazone.
Edema was reported by 4.8% of patients receiving
rosiglitazone compared with 1.3% on placebo, and 1.0% on sulfonylurea
monotherapy. The reporting rate of edema was higher for rosiglitazone 8 mg
added to a sulfonylurea (12.4%) compared with other combinations, with the
exception of insulin. Anemia was reported by 1.9% of patients receiving
rosiglitazone compared with 0.7% on placebo, 0.6% on sulfonylurea monotherapy,
and 2.3% on rosiglitazone in combination with a sulfonylurea. Overall, the
types of adverse experiences reported when rosiglitazone was added to a
sulfonylurea were similar to those during monotherapy with rosiglitazone.
In 26-week, double-blind, fixed-dose trials, edema was
reported with higher frequency in the rosiglitazone plus insulin combination
trials (insulin, 5.4%; and rosiglitazone in combination with insulin, 14.7%).
Reports of new onset or exacerbation of congestive heart failure occurred at
rates of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in
combination with rosiglitazone.
Long-term Trial of Rosiglitazone as Monotherapy: A
4- to 6-year trial (ADOPT) compared the use of rosiglitazone (n = 1,456),
glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients
recently diagnosed with type 2 diabetes who were not previously treated with
antidiabetic medication. Table 4 presents adverse reactions without regard to
causality; rates are expressed per 100 patient-years (PY) exposure to account
for the differences in exposure to trial medication across the 3 treatment
groups.
In ADOPT, fractures were reported in a greater number of
women treated with rosiglitazone (9.3%, 2.7/100 patient-years) compared with
glyburide (3.5%, 1.3/100 patient-years) or metformin (5.1%, 1.5/100
patient-years). The majority of the fractures in the women who received
rosiglitazone were reported in the upper arm, hand, and foot. The observed
incidence of fractures for male patients was similar among the 3 treatment
groups.
Table 4: On-therapy Adverse Events [ ≥ 5
Events/100 Patient-Years (PY)] in any Treatment Group Reported in a 4- to
6-Year Clinical Trial of Rosiglitazone as Monotherapy (ADOPT)
| Preferred Term |
Rosiglitazone
N = 1,456
PY = 4,954 |
Glyburide
N = 1,441
PY = 4,244 |
Metformin
N = 1,454
PY = 4,906 |
| Nasopharyngitis |
6.3 |
6.9 |
6.6 |
| Back pain |
5.1 |
4.9 |
5.3 |
| Arthralgia |
5.0 |
4.8 |
4.2 |
| Hypertension |
4.4 |
6.0 |
6.1 |
| Upper respiratory tract infection |
4.3 |
5.0 |
4.7 |
| Hypoglycemia |
2.9 |
13.0 |
3.4 |
| Diarrhea |
2.5 |
3.2 |
6.8 |
Long-term Trial of Rosiglitazone as Combination Therapy (RECORD): RECORD (Rosiglitazone
Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) was a
multicenter, randomized, open-label, non-inferiority trial in subjects with
type 2 diabetes inadequately controlled on maximum doses of metformin or
sulfonylurea (glyburide, gliclazide, or glimepiride) to compare the time to
reach the combined cardiovascular endpoint of cardiovascular death or
cardiovascular hospitalization between patients randomized to the addition of
rosiglitazone versus metformin or sulfonylurea. The trial included patients who
have failed metformin or sulfonylurea monotherapy; those who failed metformin
(n = 2,222) were randomized to receive either add-on rosiglitazone (n = 1,117)
or add-on sulfonylurea (n = 1,105), and those who failed sulfonylurea (n =
2,225) were randomized to receive either add-on rosiglitazone (n = 1,103) or
add-on metformin (n = 1,122). Patients were treated to target HbA1c ≤ 7%
throughout the trial.
The mean age of patients in this trial was 58 years, 52%
were male, and the mean duration of follow-up was 5.5 years. Rosiglitazone
demonstrated non-inferiority to active control for the primary endpoint of
cardiovascular hospitalization or cardiovascular death (HR 0.99, 95% CI:
0.85-1.16). There were no significant differences between groups for secondary
endpoints with the exception of congestive heart failure (see Table 5). The
incidence of congestive heart failure was significantly greater among patients
randomized to rosiglitazone.
Table 5: Cardiovascular (CV) Outcomes for the RECORD
Trial
| Primary Endpoint |
Rosiglitazone
N = 2,220 |
Active Control
N = 2,227 |
Hazard Ratio |
95% CI |
| CV death or CV hospitalization |
321 |
323 |
0.99 |
0.85-1.16 |
| Secondary Endpoint |
| All-cause death |
136 |
157 |
0.86 |
0.68-1.08 |
| CV death |
60 |
71 |
0.84 |
0.59-1.18 |
| Myocardial infarction |
64 |
56 |
1.14 |
0.80-1.63 |
| Stroke |
46 |
63 |
0.72 |
0.49-1.06 |
| CV death, myocardial infarction, or stroke |
154 |
165 |
0.93 |
0.74-1.15 |
| Heart failure |
61 |
29 |
2.10 |
1.35-3.27 |
There was an increased incidence of bone fracture for
subjects randomized to rosiglitazone in addition to metformin or sulfonylurea
compared with those randomized to metformin plus sulfonylurea (8.3% versus
5.3%).
The majority of fractures were reported in the upper limbs and distal lower
limbs. The risk of fracture appeared to be higher in females relative to
control (11.5% versus 6.3%), than in males relative to control (5.3% versus
4.3%). Additional data are necessary to determine whether there is an increased
risk of fracture in males after a longer period of follow-up.
Glimepiride: Approximately 2,800 patients with
type 2 diabetes have been treated with glimepiride in the controlled clinical
trials. In these trials, approximately 1,700 patients were treated with
glimepiride for at least 1 year.
Table 6 summarizes adverse events, other than
hypoglycemia, that were reported in 11 pooled placebo-controlled trials,
whether or not considered to be possibly or probably related to study
medication. Treatment duration ranged from 13 weeks to 12 months. Terms that
are reported represent those that occurred at an incidence of ≥ 5% among
glimepiride-treated patients and more commonly than in patients who received
placebo.
Table 6: Eleven Pooled Placebo-Controlled Trials
Ranging From 13 Weeks to 12 Months: Adverse Events (Excluding Hypoglycemia)
Occurring in ≥ 5% of Glimepiride-Treated Patients and at a Greater
Incidence Than With Placeboa
| Preferred Term |
Glimepiride
N = 745 % |
Placebo
N = 294 % |
| Headache |
8.2 |
7.8 |
| Accidental injuryb |
5.8 |
3.4 |
| Flu syndrome |
5.4 |
4.4 |
| Nausea |
5.0 |
3.4 |
| Dizziness |
5.0 |
2.4 |
a Glimepiride doses ranges from 1 to 16 mg
administered daily.
b Insufficient information to determine whether any of the
accidental injury events were associated with hypoglycemia. |
Hypoglycemia: In a randomized, double-blind,
placebo-controlled monotherapy trial of 14 weeks duration, patients already on
sulfonylurea therapy underwent a 3-week washout period then were randomized to
glimepiride 1 mg, 4 mg, 8 mg or placebo. Patients randomized to glimepiride 4 mg
or 8 mg underwent forced-titration from an initial dose of 1 mg to these final
doses, as tolerated. The overall incidence of possible hypoglycemia (defined by
the presence of at least one symptom that the investigator believed might be
related to hypoglycemia; a concurrent glucose measurement was not required) was
4% for glimepiride 1 mg, 17% for glimepiride 4 mg, 16% for glimepiride 8 mg,
and 0% for placebo. All of these events were self-treated.
In a randomized, double-blind, placebo-controlled
monotherapy trial of 22 weeks duration, patients received a starting dose of
either 1 mg glimepiride or placebo daily. The dose of glimepiride was titrated
to a target fasting plasma glucose of 90 to 150 mg/dL. Final daily doses of
glimepiride were 1, 2, 3, 4, 6, or 8 mg. The overall incidence of possible
hypoglycemia (as defined above for the 14-week trial) for glimepiride versus
placebo was 19.7% versus 3.2%. All of these events were self-treated.
Weight Gain: Glimepiride, like all sulfonylureas,
can cause weight gain.
Allergic Reactions: In clinical trials, allergic
reactions, such as pruritus, erythema, urticaria, and morbilliform or
maculopapular eruptions, occurred in less than 1% of glimepiride-treated
patients. These may resolve despite continued treatment with glimepiride. There
are postmarketing reports of more serious allergic reactions (e.g., dyspnea,
hypotension, shock).
Laboratory Abnormalities
Rosiglitazone
Hematologic: Decreases in mean hemoglobin and
hematocrit occurred in a dose-related fashion in adult patients treated with
rosiglitazone (mean decreases in individual trials as much as 1.0 g/dL
hemoglobin and as much as 3.3% hematocrit). The changes occurred primarily during
the first 3 months following initiation of therapy with rosiglitazone or
following a dose increase in rosiglitazone. The time course and magnitude of
decreases were similar in patients treated with a combination of rosiglitazone
and other hypoglycemic agents or monotherapy with rosiglitazone. White blood
cell counts also decreased slightly in adult patients treated with
rosiglitazone. Decreases in hematologic parameters may be related to increased
plasma volume observed with treatment with rosiglitazone.
Lipids: Changes in serum lipids have been observed
following treatment with rosiglitazone in adults.
Serum Transaminase Levels: In pre-approval
clinical trials in 4,598 patients treated with rosiglitazone encompassing
approximately 3,600 patient-years of exposure, there was no evidence of
drug-induced hepatotoxicity.
In pre-approval controlled trials, 0.2% of patients
treated with rosiglitazone had reversible elevations in ALT > 3X the upper
limit of normal compared with 0.2% on placebo and 0.5% on active comparators.
The ALT elevations in patients treated with rosiglitazone were reversible.
Hyperbilirubinemia was found in 0.3% of patients treated with rosiglitazone
compared with 0.9% treated with placebo and 1% in patients treated with active
comparators. In pre-approval clinical trials, there were no cases of
idiosyncratic drug reactions leading to hepatic failure.
In the 4- to 6-year ADOPT trial, patients treated with
rosiglitazone (4,954 patient-years exposure), glyburide (4,244 patient-years
exposure), or metformin (4,906 patient-years exposure) as monotherapy had the
same rate of ALT increase to > 3X upper limit of normal (0.3 per 100
patient-years exposure).
In the RECORD trial, patients randomized to rosiglitazone
in addition to metformin or sulfonylurea (10,849 patient-years exposure) and to
metformin plus sulfonylurea (10,209 patient-years exposure) had a rate of ALT
increase to ≥ 3X upper limit of normal of approximately 0.2 and 0.3 per
100 patient-years exposure, respectively.
Glimepiride: Serum Transaminase Levels: In 11
pooled, placebo-controlled trials of glimepiride, 1.9% of glimepiride-treated
patients and 0.8% of placebo-treated patients developed serum ALT > 2X the
upper limit of the reference range.
Postmarketing Experience
In addition to adverse reactions reported from clinical
trials, the events described below have been identified during post-approval
use of AVANDARYL or its individual components. Because these events are
reported voluntarily from a population of unknown size, it is not possible to
reliably estimate their frequency or to always establish a causal relationship
to drug exposure.
Rosiglitazone: In patients receiving thiazolidinedione therapy, serious
adverse events with or without a fatal outcome, potentially related to volume
expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions)
have been reported.
There are postmarketing reports with rosiglitazone of
hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of
normal, and hepatic failure with and without fatal outcome, although causality
has not been established.
There are postmarketing reports with rosiglitazone of
rash, pruritus, urticaria, angioedema, anaphylactic reaction, Stevens-Johnson
syndrome , and new onset or worsening diabetic
macular edema with decreased visual acuity.
Glimepiride
- Serious hypersensitivity reactions, including
anaphylaxis, angioedema, and Stevens-Johnson syndrome
- Hemolytic anemia in patients with and without G6PD
deficiency
- Impairment of liver function (e.g., with cholestasis and
jaundice), as well as hepatitis, which may progress to liver failure
- Porphyria cutanea tarda, photosensitivity reactions, and
allergic vasculitis
- Leukopenia, agranulocytosis, aplastic anemia, and
pancytopenia
- Thrombocytopenia (including severe cases with platelet
count less than 10,000/μL) and thrombocytopenic purpura
- Hepatic porphyria reactions and disulfiram-like reactions
- Hyponatremia and syndrome of inappropriate antidiuretic
hormone secretion (SIADH), most often in patients who are on other medications
or who have medical conditions known to cause hyponatremia or increase release
of antidiuretic hormone
DRUG INTERACTIONS
Drugs Metabolized By Cytochrome P450
Rosiglitazone: An inhibitor of CYP2C8 (e.g.,
gemfibrozil) may increase the AUC of rosiglitazone and an inducer of CYP2C8
(e.g., rifampin) may decrease the AUC of rosiglitazone. Therefore, if an
inhibitor or an inducer of CYP2C8 is started or stopped during treatment with
rosiglitazone, changes in diabetes treatment may be needed based upon clinical
response.
A potential interaction between oral miconazole and oral
hypoglycemic agents leading to severe hypoglycemia has been reported. Whether
this interaction also occurs with the IV, topical, or vaginal preparations of
miconazole is not known. Potential interactions of glimepiride with other drugs
metabolized by cytochrome P450 2C9 also include phenytoin, diclofenac,
ibuprofen, naproxen, and mefenamic acid.
Glimepiride: There may be an interaction between
glimepiride and inhibitors (e.g., fluconazole) and inducers (e.g., rifampin) of
CYP 2C9. Fluconazole may inhibit the metabolism of glimepiride, causing
increased plasma concentrations of glimepiride which may lead to hypoglycemia.
Rifampin may induce the metabolism of glimepiride, causing decreased plasma
concentrations of glimepiride which may lead to worsening glycemic control.
Drugs Affecting Glucose Metabolism
A number of medications affect glucose metabolism and may
require glimepiride dose adjustment and particularly close monitoring for
hypoglycemia or worsening glycemic control.
The following are examples of medications that may
increase the glucose-lowering effect of sulfonylureas including glimepiride,
increasing the susceptibility to and/or intensity of hypoglycemia: oral
anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting
enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene,
pentoxifylline, somatostatin analogs, anabolic steroids and androgens,
cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone,
tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that
are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory
drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, and
monoamine oxidase inhibitors. When these medications are administered to a
patient receiving AVANDARYL, monitor the patient closely for hypoglycemia. When
these medications are withdrawn from a patient receiving AVANDARYL, monitor the
patient closely for worsening glycemic control.
The following are examples of medications that may reduce
the glucose-lowering effect of sulfonylureas including glimepiride, leading to
worsening glycemic control: danazol, glucagon, somatropin, protease inhibitors,
atypical antipsychotic medications (e.g., olanzapine and clozapine),
barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics,
corticosteroids, phenothiazines, thyroid hormones, estrogens, oral
contraceptives, phenytoin, nicotinic acid, sympathomimetics (e.g., epinephrine,
albuterol, and terbutaline), and isoniazid. When these medications are
administered to a patient receiving AVANDARYL, monitor the patient closely for
worsening glycemic control. When these medications are withdrawn from a patient
receiving AVANDARYL, monitor the patient closely for hypoglycemia.
Beta-blockers, clonidine, and reserpine may lead to
either potentiation or weakening of glimepiride's glucose-lowering effect.
Both acute and chronic alcohol intake may potentiate or
weaken the glucose-lowering action of glimepiride in an unpredictable fashion.
The signs of hypoglycemia may be reduced or absent in
patients taking sympatholytic drugs such as beta-blockers, clonidine,
guanethidine, and reserpine.
Miconazole
A potential interaction between oral miconazole and
sulfonylureas leading to severe hypoglycemia has been reported. Whether this
interaction also occurs with other dosage forms of miconazole is not known.
Concomitant Administration Of Colesevelam
Colesevelam can reduce the maximum plasma concentration
and total exposure of glimepiride when the two are coadministered. However,
absorption is not reduced when glimepiride is administered 4 hours prior to
colesevelam. Therefore, AVANDARYL should be administered at least 4 hours prior
to colesevelam.
