Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/737
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AVANDARYL (Tablet)
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Starting Dose:<br/>Dose Titration:<br/>Maximum Dose: 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. (See INDICATIONS AND USAGE.)<br/>Specific Patient Populations:
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| dailymed-instance:descripti... |
AVANDARYL (rosiglitazone maleate and glimepiride)
tablets contain 2 oral antidiabetic drugs used in the management of
type 2 diabetes: Rosiglitazone maleate and glimepiride. Rosiglitazone maleate is an oral antidiabetic agent of
the thiazolidinedione class which acts primarily by increasing insulin
sensitivity. Rosiglitazone maleate is not chemically or functionally
related to the sulfonylureas, the biguanides, or the alpha-glucosidase
inhibitors. Chemically, rosiglitazone maleate is (��)-5-[[4-[2-(methyl-2-pyridinylamino)
ethoxy]phenyl] methyl]-2,4-thiazolidinedione, (Z)-2-butenedioate (1:1) with a molecular
weight of 473.52 (357.44 free base). The molecule has a single chiral
center and is present as a racemate. Due to rapid interconversion,
the enantiomers are functionally indistinguishable. The molecular
formula is CHNOS���CHO. Rosiglitazone maleate is a white
to off-white solid with a melting point range of 122��to 123��C.
The pKvalues of rosiglitazone maleate are 6.8 and 6.1.
It is readily soluble in ethanol and a buffered aqueous solution with
pH of 2.3; solubility decreases with increasing pH in the physiological
range. The structural formula of rosiglitazone maleate is: Glimepiride is an oral antidiabetic drug of the sulfonylurea
class. Glimepiride is a white to yellowish-white, crystalline, odorless
to practically odorless powder. Chemically, glimepiride is 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea
with a molecular weight of 490.62. The molecular formula for glimepiride
is CHNOS. Glimepiride
is practically insoluble in water. The structural formula of glimepiride
is: AVANDARYL is available for oral administration
as tablets containing rosiglitazone maleate and glimepiride, respectively,
in the following strengths (expressed as rosiglitazone maleate/glimepiride):
4 mg/1 mg, 4 mg/2 mg, 4 mg/4 mg, 8 mg/2 mg, and 8 mg/4 mg. Each tablet
contains the following inactive ingredients: Hypromellose 2910, lactose
monohydrate, macrogol (polyethylene glycol), magnesium stearate, microcrystalline
cellulose, sodium starch glycolate, titanium dioxide, and 1 or more
of the following: Yellow, red, or black iron oxides.
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Mechanism of Action: AVANDARYL combines
2 antidiabetic agents with complementary mechanisms of action to improve
glycemic control in patients with type 2 diabetes: Rosiglitazone
maleate, a member of the thiazolidinedione class, and glimepiride,
a member of the sulfonylurea class. Thiazolidinediones are insulin-sensitizing
agents that act primarily by enhancing peripheral glucose utilization,
whereassulfonylureas act primarily by stimulating release of insulin
from functioning pancreatic beta cells. Rosiglitazone
improves glycemic control by improving insulin sensitivity. Rosiglitazone
is a highly selective and potent agonist for the peroxisome proliferator-activated
receptor-gamma (PPAR��). In humans, PPAR receptors are found
in key target tissues for insulin action such as adipose tissue, skeletal
muscle, and liver. Activation of PPAR��nuclear receptors regulates
the transcription of insulin-responsive genes involved in the control
of glucose production, transport, and utilization. In addition, PPAR��-responsive
genes also participate in the regulation of fatty acid metabolism. Insulin resistance is a common feature characterizing
the pathogenesis of type 2 diabetes. The antidiabetic activity
of rosiglitazone has been demonstrated in animal models of type 2
diabetes in which hyperglycemia and/or impaired glucose tolerance
is a consequence of insulin resistance in target tissues. Rosiglitazone
reduces blood glucose concentrations and reduces hyperinsulinemia
in the ob/ob obese mouse, db/db diabetic mouse, and fa/fa fatty Zucker
rat. In animal models, the antidiabetic activity
of rosiglitazone was shown to be mediated by increased sensitivity
to insulin's action in the liver, muscle, and adipose tissues.
The expression of the insulin-regulated glucose transporter GLUT-4
was increased in adipose tissue. Rosiglitazone did not induce hypoglycemia
in animal models of type 2 diabetes and/or impaired glucose tolerance. The primary mechanism of action of glimepiride in lowering
blood glucose appears to be dependent on stimulating the release of
insulin from functioning pancreatic beta cells. In addition, extrapancreatic
effects may also play a role in the activity of sulfonylureas such
as glimepiride. This is supported by both preclinical and clinical
studies demonstrating that glimepiride administration can lead to
increased sensitivity of peripheral tissues to insulin. These findings
are consistent with the results of a long-term, randomized, placebo-controlled
trial in which glimepiride therapy improved postprandial insulin/C-peptide
responses and overall glycemic control without producing clinically
meaningful increases in fasting insulin/C-peptide levels. However,
as with other sulfonylureas, the mechanism by which glimepiride lowers
blood glucose during long-term administration has not been clearly
established.<br/>Pharmacokinetics: In a bioequivalence
study of AVANDARYL 4 mg/4 mg, the area under the curve (AUC)
and maximum concentration (C) 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 Cwas 13%
lower when administered as the combination tablet (see Table 1). AUC = area under
the curve; C= maximum concentration; T= terminal half-life; T= 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
Twhich is presented as arithmetic mean (range) and
T, 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.<br/>Absorption: The AUC
and Cof 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 Cof rosiglitazone decreased
by 32% compared to the fasted state. There was an increase in both
AUC (19%) and C(55%) of glimepiride in the fed state
compared to the fasted state.<br/>Distribution:<br/>Metabolism and Excretion:<br/>Special Populations: No pharmacokinetic
data are available for AVANDARYL in the following special populations.
Information is provided for the individual components of AVANDARYL.<br/>Gender:<br/>Geriatric:<br/>Hepatic Impairment: 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 baseline (see PRECAUTIONS, Hepatic
Effects).<br/>Race:<br/>Renal Impairment:<br/>Pediatric: No pharmacokinetic data from studies in pediatric
subjects are available for AVANDARYL.<br/>Drug Interactions: Single oral doses
of glimepiride in 14 healthy adult subjects had no clinically significant
effect on the steady-state pharmacokinetics of rosiglitazone. No clinically
significant reductions in glimepiride AUC and Cwere
observed after repeat doses of rosiglitazone (8 mg once daily) for
8 days in healthy adult subjects.<br/>Rosiglitazone:<br/>Glimepiride: The hypoglycemic
action of sulfonylureas may be potentiated by certain drugs, including
nonsteroidal anti-inflammatory drugs (NSAIDs) and other drugs that
are highly protein bound, such as salicylates, sulfonamides, chloramphenicol,
coumarins, probenecid, monoamine oxidase inhibitors, and beta-adrenergic
blocking agents. When these drugs are administered to a patient receiving
glimepiride, the patient should be observed closely for hypoglycemia.
When these drugs are withdrawn from a patient receiving glimepiride,
the patient should be observed closely for loss of glycemic control. Certain drugs tend to produce hyperglycemia and may lead
to loss of control. These drugs include the thiazides and other diuretics,corticosteroids, phenothiazines, thyroid products, estrogens, oral
contraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid.
When these drugs are administered to a patient receiving glimepiride,
the patient should be closely observed for loss of control. When these
drugs are withdrawn from a patient receiving glimepiride, the patient
should be observed closely for hypoglycemia.
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Initiation of AVANDARYL in patients with established
New York Heart Association (NYHA) Class III or IV heart failure is
contraindicated (see BOXED WARNING). AVANDARYL is contraindicated in patients
with known hypersensitivity to rosiglitazone or glimepiride or any
of the components of AVANDARYL. AVANDARYL is
contraindicated in patients with diabetic ketoacidosis, with or without
coma. This condition should be treated with insulin.
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Tablets: Each tablet contains rosiglitazone
as the maleate and glimepiride as follows: 4
mg/1 mg���yellow, rounded triangular tablet, gsk debossed on
one side and 4/1 on the other. 4 mg/2 mg���orange, rounded triangular tablet, gsk debossed on one side and 4/2
on the other. 4 mg/4 mg���pink, rounded
triangular tablet, gsk debossed on one side and 4/4 on the other. 8 mg/2 mg���pale pink, rounded triangular tablet,
gsk debossed on one side and 8/2 on the other. 8 mg/4 mg���red, rounded triangular tablet, gsk debossed on
one side and 8/4 on the other. 4 mg/1 mg bottles
of 30: NDC 0007-3151-13 4 mg/2 mg bottles of
30: NDC 0007-3152-13 4 mg/4 mg bottles of 30:
NDC 0007-3153-13 8 mg/2 mg bottles of 30: NDC
0007-3148-13 8 mg/4 mg bottles of 30: NDC 0007-3149-13
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WARNING: CONGESTIVE HEART
FAILURE:
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dailymed-ingredient:hypromellose_2910,
dailymed-ingredient:lactose_monohydrate,
dailymed-ingredient:macrogol,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:sodium_starch_glycolate,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:triacetin
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General: Due to the mechanisms
of action, rosiglitazone and glimepiride are 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.<br/>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. (See CLINICAL PHARMACOLOGY, Special Populations, Renal Impairment.) 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 (see
DOSAGE AND ADMINISTRATION, Specific Patient Populations).<br/>Loss of Control of Blood Glucose: 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.<br/>Edema: AVANDARYL should be used with caution in patients
with edema. In a clinical study 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
to 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 (see BOXED WARNING, WARNINGS,
Rosiglitazone, and PRECAUTIONS). 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 are more likely to have
adverse events associated with edema if started on combination therapy
with insulin and rosiglitazone (see ADVERSE REACTIONS). The use of
AVANDARYL in combination with insulin is not recommended (see WARNINGS,
Rosiglitazone).<br/>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. (See ADVERSE REACTIONS, Rosiglitazone.)<br/>Fractures: In a 4- to 6-year comparative study (ADOPT) of glycemic
control with monotherapy in drug-na��ve patients recently diagnosed
with type 2 diabetes mellitus, an increased incidence of bone fracture
was noted in female patients taking rosiglitazone. Over the 4- to
6-year period, the incidence of bone fracture in females was 9.3%
(60/645) for rosiglitazone versus 3.5% (21/605) for glyburide and
5.1% (30/590) for metformin. This increased incidence was noted after
the first year of treatment and persisted during the course of the
study. 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). No increase in fracture rates was observed in
men treated with rosiglitazone. The risk of fracture should be considered
in the care of patients, especially female patients, treated with
rosiglitazone, and attention given to assessing and maintaining bone
health according to current standards of care.<br/>Weight Gain: Dose-related weight gain was seen with AVANDARYL,
rosiglitazone alone, and rosiglitazone together with other hypoglycemic
agents (see Table 5). The mechanism of weight gain is unclear but
probably involves a combination of fluid retention and fat accumulation. 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 (see BOXED WARNING).<br/>Hematologic: Across all controlled clinical studies, decreases
in hemoglobin and hematocrit (mean decreases in individual studies���1.0 gram/dL and���3.3%, respectively) were observed
for rosiglitazone alone and in combination with other hypoglycemic
agents. The changes occurred primarily during the first 3 months
following initiation of therapy with rosiglitazone or following a
dose increase in rosiglitazone. White blood cell counts also decreased
slightly in patients treated with rosiglitazone. The observed changes
may be related to the increased plasma volume observed with treatment
with rosiglitazone and may be dose related.<br/>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 (see PRECAUTIONS, Pregnancy, Pregnancy
Category C). Thus, adequate contraception in premenopausal women should
be recommended. This possible effect has not been specifically investigated
in clinical studies so the frequency of this occurrence is not known. Although hormonal imbalance has been seen in preclinical
studies (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment
of Fertility), the clinical significance of this finding is not known.
If unexpected menstrual dysfunction occurs, the benefits of continued
therapy with AVANDARYL should be reviewed.<br/>Hepatic Effects: Another drug of the thiazolidinedione class, troglitazone,
was associated with idiosyncratic hepatotoxicity, and very rare cases
of liver failure, liver transplants, and death were reported during
clinical use. In pre-approval controlled clinical trials in patients
with type 2 diabetes, troglitazone was more frequently associated
with clinically significant elevations in liver enzymes (ALT>3X upper
limit of normal) compared to placebo. Very rare cases of reversible
jaundice were also reported. In pre-approval
clinical studies in 4,598 patients treated with rosiglitazone, encompassing
approximately 3,600 patient years of exposure, there was no signal
of drug-induced hepatotoxicity or elevation of ALT levels. In the
pre-approval controlled trials, 0.2% of patients treated with rosiglitazone
had elevations in ALT>3X the upper limit of normal compared to 0.2%
on placebo and 0.5% on active comparators. The ALT elevations in patients
treated with rosiglitazone were reversible and were not clearly causally
related to therapy with rosiglitazone. In postmarketing
experience with rosiglitazone, reports of hepatitis and of hepatic
enzyme elevations to 3 or more times the upper limit of normal have
been received. Very rarely, these reports have involved hepatic failure
with and without fatal outcome, although causality has not been established.
Rosiglitazone is structurally related to troglitazone, a thiazolidinedione
no longer marketed in the United States, which was associated with
idiosyncratic hepatotoxicity and rare cases of liver failure, liver
transplants, and death during clinical use. Pending the availability
of the results of additional large, long-term controlled clinical
trials and additional postmarketing safety data, it is recommended
that patients treated with AVANDARYL undergo periodic monitoring of
liver enzymes. 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 checked prior to the initiation of therapy with
AVANDARYL in all patients and periodically thereafter per the clinical
judgement 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
judgement pending laboratory evaluations. If jaundice is observed,
drug therapy should be discontinued. There are
no data available from clinical trials to evaluate the safety of AVANDARYL
in patients who experienced liver abnormalities, hepatic dysfunction,
or jaundice while on troglitazone. AVANDARYL should not be used in
patients who experienced jaundice while taking troglitazone.<br/>Laboratory Tests: Periodic fasting
glucose and HbA1c measurements should be performed to monitor therapeutic
response. Liver enzyme monitoring is recommended
prior to initiation of therapy with AVANDARYL in all patients and
periodically thereafter (see PRECAUTIONS, Hepatic Effects).<br/>Information for Patients: Patients should
be informed of the potential risks and advantages of AVANDARYL and
of alternative modes of therapy. They should also be informed about
the importance of adherence to dietary instructions, weight loss,
and a regular exercise program because these methods help improve
insulin sensitivity. The importance of regular testing of blood glucose
and glycosylated hemoglobin (HbA1c) should be emphasized. Patients
should be advised that the sulfonylurea effect of AVANDARYL can begin
to takeeffect within days after initiation, however it can take 2
to 3 months to see the full effect of glycemic improvement. The risks of hypoglycemia, its symptoms and treatment,
and conditions that predispose to its development should be explained
to patients and their family members. Patients
should be informed that blood will be drawn to check their liver function
prior to the start of therapy and periodically thereafter per the
clinical judgement 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 (see PRECAUTIONS, Pregnancy,
Pregnancy Category C). Thus, adequate contraception in premenopausal
women should be recommended. This possible effect has not been specifically
investigated in clinical studies so the frequency of this occurrence
is not known.<br/>Drug Interactions:<br/>Rosiglitazone: Drugs Metabolized by
Cytochrome P450 An inhibitor of CYP2C8 (such as gemfibrozil) may increase
the AUC of rosiglitazone and an inducer of CYP2C8 (such as 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. (See CLINICAL PHARMACOLOGY, Drug Interactions, Rosiglitazone.)<br/>Glimepiride: Certain
drugs tend to produce hyperglycemia and may lead to loss of control.
These drugs include the thiazides and other diuretics, corticosteroids,
phenothiazines, thyroid products, estrogens, oral contraceptives,
phenytoin, nicotinic acid, sympathomimetics, and isoniazid. When these
drugs are administered to a patient receiving glimepiride, the patient
should be closely observed for loss of control. When these drugs are
withdrawn from a patient receiving glimepiride, the patient should
be observed closely for hypoglycemia. 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. (See CLINICAL PHARMACOLOGY,
Drug Interactions, Glimepiride.)<br/>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.<br/>Rosiglitazone:<br/>Glimepiride:<br/>Animal Toxicology:<br/>Rosiglitazone: Heart
weights were increased in mice (3 mg/kg/day), rats (5 mg/kg/day),
and dogs (2 mg/kg/day) with rosiglitazone treatments (approximately
5, 22, and 2 times human AUC at the maximum recommended human
daily dose, respectively). Effects in juvenile rats were consistent
with those seen in adults. Morphometric measurement indicated that
there was hypertrophy in cardiac ventricular tissues, which may be
due to increased heart work as a result of plasma volume expansion.<br/>Glimepiride: Reduced
serum glucose values and degranulation of the pancreatic beta cells
were observed in beagle dogs exposed to glimepiride 320 mg/kg/day
for 12 months (approximately 1,000 times the recommended
human dose based on surface area). No evidence of tumor formation
was observed in any organ. One female and one male dog developed bilateral
subcapsular cataracts. Non-GLP studies indicated that glimepiride
was unlikely to exacerbate cataract formation. Evaluation of the co-cataractogenic
potential of glimepiride in several diabetic and cataract rat models
was negative and there was no adverse effect of glimepiride on bovine
ocular lens metabolism in organ culture (see ADVERSE EVENTS, Human Ophthalmology Data).<br/>Pregnancy: Pregnancy Category
C. Because current information
strongly suggests that abnormal blood glucose levels during pregnancy
are associated with a higher incidence of congenital anomalies as
well as increased neonatal morbidity and mortality, most experts recommend
that insulin monotherapy be used during pregnancy to maintain blood
glucose levels as close to normal as possible. AVANDARYL should not
be used during pregnancy. There are no adequate
and well-controlled studies with AVANDARYL or its individual components
in pregnant women. No animal studies have been conducted with AVANDARYL.
The following data are based on findings in studies performed with
rosiglitazone or glimepiride individually.<br/>Rosiglitazone: Rosiglitazone has been reported to cross the human
placenta and be detectable in fetal tissue. The clinical significance
of these findings is unknown. 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.<br/>Glimepiride: Glimepiride
did not produce teratogenic effects in rats exposed orally up to 4,000
mg/kg body weight (approximately 4,000 times the maximum recommended
human dose based on surface area) or in rabbits exposed up to 32 mg/kg
body weight (approximately 60 times the maximum recommended human
dose based on surface area). Glimepiride has been shown to be associated
with intrauterine fetal death in rats when given in doses as lowas
50 times the human dose based on surface area and in rabbits
when given in doses as low as 0.1 times the human dose based
on surface area. This fetotoxicity, observed only at doses inducing
maternal hypoglycemia, has been similarly noted with other sulfonylureas,
and is believed to be directly related to the pharmacologic (hypoglycemic)
action of glimepiride. In some studies in rats,
offspring of dams exposed to high levels of glimepiride during pregnancy
and lactation developed skeletal deformities consisting of shortening,
thickening, and bending of the humerus during the postnatal period.
Significant concentrations of glimepiride were observed in the serum
and breast milk of the dams as well as in the serum of the pups. These
skeletal deformations were determined to be the result of nursing
from mothers exposed to glimepiride. Prolonged severe hypoglycemia
(4 to 10 days) has been reported in neonates born to mothers who were
receiving a sulfonylurea drug at the time of delivery. This has been
reported more frequently with the use of agents with prolonged half-lives.<br/>Labor and Delivery: The effect of
AVANDARYL or its components on labor and delivery in humans is unknown.<br/>Nursing Mothers: No studies have
been conducted with AVANDARYL. It is not known whether rosiglitazone
and/or glimepiride is excreted in human milk. Because many drugs are
excreted in human milk, AVANDARYL should not be administered to a
nursing woman. If AVANDARYL is discontinued, and if diet alone is
inadequate for controlling blood glucose, insulin therapy should be
considered (see PRECAUTIONS, Pregnancy, Pregnancy Category C).<br/>Rosiglitazone: Drug-related
material was detected in milk from lactating rats.<br/>Glimepiride: In rat reproduction studies, significant concentrations
of glimepiride were observed in the serum and breast milk of the dams,
as well as in the serum of the pups. Although it is not known whether
glimepiride is excreted in human milk, other sulfonylureas are excreted
in human milk.<br/>Pediatric Use: Safety and effectiveness of AVANDARYL in pediatric
patients have not been established. AVANDARYL and its components,
rosiglitazone and glimepiride, are not indicated for use in pediatric
patients.<br/>Geriatric Use:<br/>Rosiglitazone: Results of the population pharmacokinetic analysis
showed that age does not significantly affect the pharmacokinetics
of rosiglitazone (see CLINICAL PHARMACOLOGY, Special Populations, Geriatric ). Therefore, no dosage adjustments
are required for the elderly. In controlled clinical trials, no overall
differences in safety and effectiveness between older (���65
years) and younger (<65 years) patients were observed.<br/>Glimepiride: In US clinical
studies of glimepiride, 608 of 1,986 patients were 65 and older. No
overall differences in safety or effectiveness were observed between
these subjects and younger subjects, but greater sensitivity of some
older individuals cannot be ruled out. Comparison
of glimepiride pharmacokinetics in type 2 diabetes patients���65
years (n = 49) and those>65 years (n = 42) was
performed in a study using a dosing regimen of 6 mg daily. There were
no significant differences in glimepiride pharmacokinetics between
the 2 age groups (see CLINICAL PHARMACOLOGY, Special Populations, Geriatric). The
drug is known to be substantially excreted by the kidney, and the
risk of toxic reactions to this drug may be greater in patients with
impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection,
and it may be useful to monitor renal function. Elderly patients are particularly susceptible to hypoglycemic action
of glucose-lowering drugs. In elderly, debilitated, or malnourished
patients, or in patients with renal, hepatic or adrenal insufficiency,
the starting dose, dose increments, and maintenance dosage should
be conservative based upon blood glucose levels prior to and after
initiation of treatment to avoid hypoglycemic reactions. Hypoglycemia
may be difficult to recognize in the elderly and in people who are
taking beta-adrenergic blocking drugs or other sympatholytic agents
(see CLINICAL PHARMACOLOGY, Special Populations,Renal Impairment; PRECAUTIONS, General;and DOSING AND ADMINISTRATION, Special Populations).
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| dailymed-instance:overdosag... |
Rosiglitazone: Limited data
are available with regard to overdosage in humans. In clinical studies
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.<br/>Glimepiride: Overdosage of
sulfonylureas, including glimepiride, can produce hypoglycemia. Mild
hypoglycemic symptoms without loss of consciousness or neurologic
findings should be treated aggressively with oral glucose and adjustments
in drug dosage and/or meal patterns. Close monitoring should continue
until the physician is assured that the patient is out of danger.
Severe hypoglycemic reactions with coma, seizure, or other neurological
impairmentoccur infrequently, but constitute medical emergencies
requiring immediate hospitalization. If hypoglycemic coma is diagnosed
or suspected, the patient should be given a rapid IV injection of
concentrated (50%) glucose solution. This should be followed by a
continuous infusion of a more dilute (10%) glucose solution at a rate
that will maintain the blood glucose level above 100 mg/dL. Patients
should be closely monitored for a minimum of 24 to 48 hours, because
hypoglycemia may recur after apparent clinical recovery.
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| dailymed-instance:genericMe... |
rosiglitazone maleate and glimepiride
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| dailymed-instance:fullName |
AVANDARYL (Tablet)
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| dailymed-instance:adverseRe... |
Adverse events occurring at a frequency of���5%
in any treatment group in the 28-week double-blind trial of AVANDARYL
in drug-na��ve patients with type 2 diabetes mellitus are presented
in Table 6. 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
6. Adverse Events (���5% in Any Treatment Group) Reported by
Drug-Na��ve Patients in a 28-Week Double-Blind Clinical Trial of AVANDARYL 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 study. 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. Studies 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 as monotherapy, are presented
below.<br/>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
studies 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 to 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 to other combinations, with
the exception of insulin. Anemia was reported by 1.9% of patients
receiving rosiglitazone compared to 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 studies, 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 (see BOXED WARNING and WARNINGS, Rosiglitazone). In postmarketing experience in patients receiving thiazolidinedione
therapy, serious adverse events potentially related to volume expansion
(e.g., congestive heart failure, pulmonary edema with or without a
fatal outcome, and pleural effusions) have been reported (see BOXED
WARNING and WARNINGS, Rosiglitazone). In postmarketing
experience with rosiglitazone, rash, pruritus, urticaria, angioedema
and anaphylactic reaction have been reported rarely. Postmarketing reports of new onset or worsening diabetic macular
edema with decreased visual acuity have also been received (see PRECAUTIONS,
Macular Edema).<br/>Glimepiride:<br/>Hypoglycemia: The incidence of hypoglycemia with glimepiride, as
documented by blood glucose values<60 mg/dL, ranged from 0.9%
to 1.7% in 2 large, well-controlled, 1-year studies. In patients treated
with glimepiride in US placebo-controlled trials (n = 746),
adverse events, other than hypoglycemia, considered to be possibly
or probably related to study drug that occurred in more than 1% of
patients included dizziness (1.7%), asthenia (1.6%), headache (1.5%),
and nausea (1.1%).<br/>Gastrointestinal Reactions: Vomiting, gastrointestinal pain, and diarrhea have
been reported, but the incidence in placebo-controlled trials was
less than 1%. In rare cases, there may be an elevation of liver enzyme
levels. 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 with sulfonylureas, including
glimepiride.<br/>Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema,
urticaria, and morbilliform or maculopapular eruptions, occur in less
than 1% of treated patients. These may be transient and may disappear
despite continued use of glimepiride. If those hypersensitivity reactions
persist or worsen, the drug should be discontinued. Porphyria cutanea
tarda, photosensitivity reactions, and allergic vasculitis have been
reportedwith sulfonylureas, including glimepiride.<br/>Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic
anemia, aplastic anemia, and pancytopenia have been reported with
sulfonylureas, including glimepiride.<br/>Metabolic Reactions: Hepatic porphyria reactions and disulfiram-like reactions
have been reported with sulfonylureas, including glimepiride. Cases
of hyponatremia have been reported with glimepiride and all other
sulfonylureas, most often in patients who are on other medications
or have medical conditions known to cause hyponatremia or increaserelease of antidiuretic hormone. The syndrome of inappropriate antidiuretic
hormone (SIADH) secretion has been reported with certain other sulfonylureas,
including glimepiride, and it has been suggested that certain sulfonylureas
may augment the peripheral (antidiuretic) action of ADH and/or increase
release of ADH.<br/>Other Reactions: Changes in accommodation and/or blurred vision may
occur with the use of glimepiride. This is thought to be due to changes
in blood glucose, and may be more pronounced when treatment is initiated.
This condition is also seen in untreated diabetic patients, and may
actually be reduced by treatment. In placebo-controlled trials of
glimepiride, the incidence of blurred vision was placebo, 0.7%, and
glimepiride, 0.4%.<br/>Human Ophthalmology Data: Ophthalmic examinations were carried out in more
than 500 subjects during long-term studies of glimepiride using the
methodology of Taylor and West and Laties et al. No significant differences
were seen between glimepiride and glyburide in the number of subjects
with clinically important changes in visual acuity, intraocular tension,
or in any of the 5 lens-related variables examined. Ophthalmic examinations
were carried out during long-term studies using the method of Chylack
et al. No significant or clinically meaningful differences were seen
between glimepiride and glipizide with respect to cataract progression
by subjective LOCS II grading and objective image analysis systems,
visual acuity, intraocular pressure, and general ophthalmic examination
(see PRECAUTIONS, Animal Toxicology, Glimepiride).<br/>Pediatric Use: Safety and effectiveness of AVANDARYL in pediatric
patients have not been established. AVANDARYL and its individual components,
rosiglitazone and glimepiride, are not indicated for use in pediatric
patients.
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| dailymed-instance:warning |
Glimepiride: SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY 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 trialdesigned 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 (Diabetes 1970;19[Suppl. 2]:747-830). 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
2��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-containing tablets and of alternativemodes 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.<br/>Rosiglitazone:<br/>Cardiac Failure and Other
Cardiac Effects: 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 (see BOXED WARNING). In combination with insulin,
thiazolidinediones may also increase the risk of other cardiovascular
adverse events. Rosiglitazone should be discontinued if any deterioration
in cardiac status occurs. 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 study 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 to placebo during
the 52-week study. (See Table 4.) Table 4. 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) Includes hospitalization
for any cardiovascular reason. 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. (See BOXED WARNING.) Patients with NYHA Class III and IV cardiac status were not
studied during the clinical trials. Rosiglitazone is not recommended
in patients with NYHA Class III and IV cardiac status. In three 26-week trials in patients with type 2 diabetes,
216 received 4 mg of rosiglitazone plus insulin, 322 received
8 mg of rosiglitazone plus insulin, and 338 received insulin
alone. These trials included patients with long-standing diabetes
and a high prevalence of pre-existing medical conditions, including
peripheral neuropathy, retinopathy, ischemic heart disease, vascular
disease, and congestive heart failure. In these clinical studies an
increased incidence of edema, cardiac failure, and other cardiovascular
adverse events was seen in patients on rosiglitazone and insulin combination
therapy compared to insulin and placebo. Patients who experienced
cardiovascular events were on average older and had a longer duration
of diabetes. These cardiovascular events were noted at both the 4 mg
and 8 mg daily doses of rosiglitazone. In this population, however,
it was not possible to determine specific risk factors that could
be used to identify all patients at risk of heart failure and other
cardiovascular events on combination therapy. Three of 10 patients
who developed cardiac failure on combination therapy during the double-blind
part of the fixed-dose studies had no known prior evidence of congestive
heart failure, or pre-existing cardiac condition. In a double-blind study in type 2 diabetes patients with chronic
renal failure (112 received 4 mg or 8 mg of rosiglitazone
plus insulin and 108 received insulin control), there was no difference
in cardiovascular adverse events with rosiglitazone in combination
with insulin compared to insulin control. Patientstreated with combination rosiglitazone and insulin should be monitored
for cardiovascular adverse events. This combination therapy should
be discontinued in patients who do not respond as manifested by a
reduction in HbA1c or insulin dose after 4 to 5 months of therapy
or who develop any significant adverse events. (See ADVERSE REACTIONS.) There are no studies that have evaluated the safety or
effectiveness of AVANDARYL in combination with insulin. Therefore,
the use of AVANDARYL in combination with insulin is not recommended.
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| dailymed-instance:indicatio... |
AVANDARYL is indicated as an adjunct to diet and
exercise, to improve glycemic control in patients with type 2
diabetes mellitus when treatment with dual rosiglitazone and glimepiride
therapy is appropriate. 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. Prior to initiation of
therapy with AVANDARYL, secondary causes of poor glycemic control,
e.g., infection, should be investigated and treated.
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| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
AVANDARYL
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