ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
AVANDAMET 1 mg/500 mg film-coated tablets
2.
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Excipients:
Each tablet contains lactose (approximately 6 mg).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Yellow film-coated tablets marked "gsk" on one side and "1/500" on the other.
4.
AVANDAMET is indicated in the treatment of type 2 diabetes mellitus patients, particularly
overweight patients:
-
who are unable to achieve sufficient glycaemic control at their maximally tolerated dose of oral
metformin alone.
-
in triple oral therapy with sulphonylurea in patients with insufficient glycaemic control despite
dual oral therapy with their maximally tolerated dose of metformin and a sulphonylurea (see
section 4.4).
The usual starting dose of AVANDAMET is 4 mg/day rosiglitazone plus 2000 mg/day metformin
hydrochloride.
Rosiglitazone can be increased to 8 mg/day after 8 weeks if greater glycaemic control is required. The
maximum recommended daily dose of AVANDAMET is 8 mg rosiglitazone plus 2000 mg metformin
hydrochloride.
The total daily dose of AVANDAMET should be given in two divided doses.
Dose titration with rosiglitazone (added to the optimal dose of metformin) may be considered before
the patient is switched to AVANDAMET.
When clinically appropriate, direct change from metformin monotherapy to AVANDAMET may be
considered.
Taking AVANDAMET with or just after food may reduce gastrointestinal symptoms associated with
metformin.
Triple oral therapy (rosiglitazone, metformin and sulphonylurea) (see section 4.4)
2
Each tablet contains 1 mg of rosiglitazone (as rosiglitazone maleate) and 500 mg of metformin
hydrochloride (corresponding to metformin free base 390 mg).
-
Patients on metformin and sulphonylurea: when appropriate AVANDAMET may be initiated at
4 mg/day rosiglitazone with the dose of metformin substituting that already being taken. An
increase in the rosiglitazone component to 8 mg/day should be undertaken cautiously following
appropriate clinical evaluation to assess the patient's risk of developing adverse reactions
relating to fluid retention (see sections 4.4 and 4.8).
-
Patients established on triple oral therapy: when appropriate, AVANDAMET may substitute
rosiglitazone and metformin doses already being taken.
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Elderly
As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal
function, elderly patients taking AVANDAMET should have their renal function monitored regularly
(see sections 4.3 and 4.4).
Patients with renal impairment
AVANDAMET should not be used in patients with renal failure or renal dysfunction, e.g. serum
creatinine levels > 135 μmol/l in males and > 110 μmol/l in females and/or creatinine clearance
< 70 ml/min (see sections 4.3 and 4.4).
Children and adolescents
AVANDAMET is not recommended for use in children and adolescents below 18 years of age as
there are no data available on its safety and efficacy in this age group (see sections 5.1 and 5.2).
AVANDAMET is contraindicated in patients with:
-
hypersensitivity to rosiglitazone, to metformin hydrochloride or to any of the excipients
-
cardiac failure or history of cardiac failure (New York Heart Association (NYHA) stages I to
IV)
-
an Acute Coronary Syndrome (unstable angina, NSTEMI and STEMI) (see section 4.4)
-
acute or chronic disease which may cause tissue hypoxia such as:
-
cardiac or respiratory failure
-
recent myocardial infarction
-
shock
-
hepatic impairment
-
acute alcohol intoxication, alcoholism (see section 4.4)
-
diabetic ketoacidosis or diabetic pre-coma
-
renal failure or renal dysfunction e.g. serum creatinine levels > 135 µmol/l in males and
> 110 µmol/l in females and/or creatinine clearance < 70 ml/min (see section 4.4)
-
acute conditions with the potential to alter renal function such as:
-
dehydration
-
severe infection
-
shock
-
intravascular administration of iodinated contrast agents (see section 4.4)
-
lactation.
Lactic acidosis
Lactic acidosis is a very rare, but serious, metabolic complication that can occur due to metformin
accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in
diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be
reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis,
3
Where appropriate, AVANDAMET may be used to substitute concomitant rosiglitazone and
metformin in existing dual or triple oral therapy to simplify treatment.
prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with
hypoxia.
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Renal function
As metformin is excreted by the kidney, serum creatinine concentrations should be determined
regularly:
-
at least once a year in patients with normal renal function
-
at least two to four times a year in patients with serum creatinine levels at the upper limit of
normal and in elderly patients.
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be
exercised in situations where renal function may become impaired, for example when initiating
antihypertensive or diuretic therapy or when starting treatment with an NSAID.
Fluid retention and cardiac failure
Thiazolidinediones can cause fluid retention which may exacerbate or precipitate signs or symptoms
of congestive heart failure. Rosiglitazone can cause dose-dependent fluid retention. The possible
contribution of fluid retention to weight gain should be individually assessed as rapid and excessive
weight gain has been reported very rarely as a sign of fluid retention. All patients, particularly those
receiving concurrent insulin but also sulphonylurea therapy, those at risk for heart failure, and those
with reduced cardiac reserve, should be monitored for signs and symptoms of adverse reactions
relating to fluid retention, including weight gain and heart failure. AVANDAMET must be
discontinued if any deterioration in cardiac status occurs.
The use of AVANDAMET in combination with a sulphonylurea or insulin may be associated with
increased risks of fluid retention and heart failure (see section 4.8). The decision to initiate
AVANDAMET in combination with a sulphonylurea should include consideration of alternative
therapies. Increased monitoring of the patient is recommended if AVANDAMET is used in
combination particularly with insulin but also with a sulphonylurea.
Heart failure was also reported more frequently in patients with a history of heart failure; oedema and
heart failure was also reported more frequently in elderly patients and in patients with mild or
moderate renal failure. Caution should be exercised in patients over 75 years because of the limited
experience in this patient group. Since NSAIDs, insulin and rosiglitazone are all associated with fluid
retention, concomitant administration may increase the risk of oedema.
Combination with insulin
An increased incidence of cardiac failure has been observed in clinical trials when rosiglitazone is
used in combination with insulin. Insulin and rosiglitazone are both associated with fluid retention,
concomitant administration may increase the risk of oedema and could increase the risk of ischaemic
heart disease. Insulin should only be added to established rosiglitazone therapy in exceptional cases
and under close supervision.
Myocardial Ischaemia
A retrospective analysis of data from 42 pooled short-term clinical studies indicated that treatment
with rosiglitazone may be associated with an increased risk of myocardial ischaemic events. However,
in their entirety the available data on the risk of cardiac ischaemia are inconclusive (see section 4.8).
There are limited clinical trial data in patients with ischaemic heart disease and/or peripheral arterial
disease. Therefore, as a precaution, the use of rosiglitazone is not recommended in these patients,
particularly those with myocardial ischaemic symptoms.
4
Diagnosis:
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by
coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l
and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment
with the medicinal product should be discontinued and the patient hospitalised immediately (see
section 4.9).
Acute Coronary Syndrome (ACS)
Patients experiencing an ACS have not been studied in rosiglitazone controlled clinical trials. In view
of the potential for development of heart failure in these patients, rosiglitazone should therefore not be
initiated in patients having an acute coronary event and it should be discontinued during the acute
phase (see section 4.3).
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Eye disorders
Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual
acuity have been reported with thiazolidinediones, including rosiglitazone. Many of these patients
reported concurrent peripheral oedema. It is unclear whether or not there is a direct association
between rosiglitazone and macular oedema but prescribers should be alert to the possibility of macular
oedema if patients report disturbances in visual acuity and appropriate ophthalmologic referral should
be considered.
Weight gain
In clinical trials with rosiglitazone there was evidence of dose-related weight gain, which was greater
when used in combination with insulin. Therefore weight should be closely monitored, given that it
may be attributable to fluid retention, which may be associated with cardiac failure.
Anaemia
Rosiglitazone treatment is associated with a dose-related reduction of haemoglobin levels. In patients
with low haemoglobin levels before initiating therapy, there is an increased risk of anaemia during
treatment with AVANDAMET.
Hypoglycaemia
Patients receiving AVANDAMET in combination with a sulphonylurea or insulin may be at risk for
dose-related hypoglycaemia. Increased monitoring of the patient and a reduction in the dose of the
concomitant agent may be necessary.
Surgery
As AVANDAMET contains metformin hydrochloride, the treatment should be discontinued 48 hours
before elective surgery with general anaesthesia and should not usually be resumed earlier than 48
hours afterwards.
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast agents in radiological studies can lead to renal
failure. Therefore, due to the metformin active substance, AVANDAMET should be discontinued
prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal
function has been re-evaluated and found to be normal (see section 4.5).
Bone disorders
5
Monitoring of liver function
There have been rare reports of hepatocellular dysfunction during post-marketing experience with
rosiglitazone (see section 4.8). There is limited experience with rosiglitazone in patients with elevated
liver enzymes (ALT > 2.5 times the upper limit of normal). Therefore, liver enzymes should be
checked prior to the initiation of therapy with AVANDAMET in all patients and periodically
thereafter based on clinical judgement. Therapy with AVANDAMET should not be initiated in
patients with increased baseline liver enzyme levels (ALT > 2.5 times the upper limit of normal) or
with any other evidence of liver disease. If ALT levels are increased to > 3 times the upper limit of
normal during AVANDAMET therapy, liver enzyme levels should be reassessed as soon as possible.
If ALT levels remain > 3 times the upper limit of normal, therapy 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 AVANDAMET should be guided by clinical
judgement pending laboratory evaluations. If jaundice is observed, therapy should be discontinued.
Long-term studies show an increased incidence of bone fractures in patients, particularly female
patients, taking rosiglitazone (see section 4.8). The majority of the fractures have occurred in the upper
limbs and distal lower limbs. In females, this increased incidence was noted after the first year of
treatment and persisted during long-term treatment. The risk of fracture should be considered in the
care of patients, especially female patients, treated with rosiglitazone.
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AVANDAMET should be used with caution during concomitant administration of CYP2C8 inhibitors
(e.g. gemfibrozil) or inducers (e.g. rifampicin), due to the effect on rosiglitazone pharmacokinetics
(see section 4.5). Furthermore, AVANDAMET should be used with caution during concomitant
administration of cationic medicinal products that are eliminated by renal tubular secretion (e.g.
cimetidine) due to the effect on metformin pharmacokinetics (see section 4.5). Glycaemic control
should be monitored closely. AVANDAMET dose adjustment within the recommended posology or
changes in diabetic treatment should be considered.
All patients should continue their diet with regular distribution of carbohydrate intake during the day.
Overweight patients should continue their energy-restricted diet.
The usual laboratory tests for diabetes monitoring should be performed regularly.
AVANDAMET tablets contain lactose and therefore should not be administered to patients with rare
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption.
There have been no formal interaction studies for AVANDAMET, however the concomitant use of the
active substances in patients in clinical studies and in widespread clinical use has not resulted in any
unexpected interactions. The following statements reflect the information available on the individual
active substances (rosiglitazone and metformin).
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of
fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of
AVANDAMET (see section 4.4). Avoid consumption of alcohol and medicinal products containing
alcohol.
Cationic medicinal products that are eliminated by renal tubular secretion (e.g. cimetidine) may
interact with metformin by competing for common renal tubular transport systems. A study conducted
in seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily,
increased metformin systemic exposure (AUC) by 50% and C
max
by 81%. Therefore, close monitoring
of glycaemic control, dose adjustment within the recommended posology and changes in diabetic
treatment should be considered when cationic medicinal products that are eliminated by renal tubular
secretion are co-administered (see section 4.4).
In vitro
studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with
CYP2C9 as only a minor pathway.
Co-administration of rosiglitazone with gemfibrozil (an inhibitor of CYP2C8) resulted in a twofold
increase in rosiglitazone plasma concentrations. Since there is a potential for an increase in the risk of
dose-related adverse reactions, a decrease in rosiglitazone dose may be needed. Close monitoring of
glycaemic control should be considered (see section 4.4).
6
Other precautions
Premenopausal women have received rosiglitazone during clinical studies. Although hormonal
imbalance has been seen in preclinical studies (see section 5.3), no significant undesirable effects
associated with menstrual disorders have been observed. As a consequence of improving insulin
sensitivity, resumption of ovulation may occur in patients who are anovulatory due to insulin
resistance. Patients should be aware of the risk of pregnancy (see section 4.6).
Co-administration of rosiglitazone with rifampicin (an inducer of CYP2C8) resulted in a 66% decrease
in rosiglitazone plasma concentrations. It cannot be excluded that other inducers (e.g. phenytoin,
carbamazepine, phenobarbital, St John’s wort) may also affect rosiglitazone exposure. The
rosiglitazone dose may need to be increased. Close monitoring of glycaemic control should be
considered (see section 4.4).
Clinically significant interactions with CYP2C9 substrates or inhibitors are not anticipated.
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No clinically relevant interactions with digoxin, the CYP2C9 substrate warfarin, the CYP3A4
substrates nifedipine, ethinylestradiol or norethindrone were observed after co-administration with
rosiglitazone.
Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in
metformin accumulation and a risk of lactic acidosis. Metformin should be discontinued prior to, or at
the time of the test and not reinstituted until 48 hours afterwards and only after renal function has been
re-evaluated and found to be normal.
Combination requiring precautions for use
Glucocorticoids (given by systemic and local routes) beta-2-agonists, and diuretics have intrinsic
hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring
performed, especially at the beginning of treatment. If necessary, the dosage of the
antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal
product and on its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. If necessary, the dosage of the
antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal
product and on its discontinuation.
For AVANDAMET no preclinical or clinical data on exposed pregnancies or lactation are available.
Rosiglitazone has been reported to cross the human placenta and to be detectable in foetal tissues.
There are no adequate data from the use of rosiglitazone in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Therefore, AVANDAMET should not be used during pregnancy. If a patient wishes to become
pregnant or if pregnancy occurs, treatment with AVANDAMET should be discontinued unless the
expected benefit to the mother outweighs the potential risk to the foetus.
Both rosiglitazone and metformin have been detected in the milk of experimental animals. It is not
known whether breast-feeding will lead to exposure of the infant to the medicinal product.
AVANDAMET must therefore not be used in women who are breast-feeding (see section 4.3).
AVANDAMET has no or negligible influence on the ability to drive and use machines.
Adverse reactions are presented below for each of the component parts of AVANDAMET. An adverse
reaction is only presented for the fixed dose combination if it has not been seen in one of the
component parts of AVANDAMET or if it occurred at a higher frequency than that listed for a
component part.
7
Concomitant administration of rosiglitazone with the oral antihyperglycaemic agents glibenclamide
and acarbose did not result in any clinically relevant pharmacokinetic interactions.
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AVANDAMET
Data from double-blind studies confirm that the safety profile of concomitant rosiglitazone and
metformin is similar to that of the combined adverse reaction profile for the two medicinal products.
Data with AVANDAMET is also consistent with this combined adverse reaction profile.
Clinical trial data (addition of insulin to established AVANDAMET therapy)
In a single study (n=322) where insulin was added to patients established on AVANDAMET, no new
adverse events were observed in excess of those already defined for either AVANDAMET or
rosiglitazone combination therapies.
However, the risk of both fluid related adverse events and hypoglycaemia are increased when
AVANDAMET is used in combination with insulin.
Rosiglitazone
Clinical trial data
Adverse reactions for each treatment regimen are presented below by system organ class and absolute
frequency. For dose-related adverse reactions the frequency category reflects the higher dose of
rosiglitazone. Frequency categories do not account for other factors including varying study duration,
pre-existing conditions and baseline patient characteristics.
Table 1 lists adverse reactions identified from an overview of clinical trials involving over 5,000
rosiglitazone-treated patients. Within each system organ class, adverse reactions are presented in the
table by decreasing frequency for the rosiglitazone monotherapy treatment regimen. Within each
frequency grouping, adverse reactions are presented in order of decreasing seriousness.
8
Adverse reactions for each treatment regimen are presented below by system organ class and absolute
frequency. For dose-related adverse reactions the frequency category reflects the higher dose of
rosiglitazone. Frequency categories do not account for other factors including varying study duration,
pre-existing conditions and baseline patient characteristics. Adverse reaction frequency categories
assigned based on clinical trial experience may not reflect the frequency of adverse events occurring
during normal clinical practice. Frequencies are defined as: very common (≥1/10), common (≥1/100 to
<1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000) and very rare (<1/10,000
including isolated reports).
Table 1. The frequency of adverse reactions identified from clinical trial data with rosiglitazone
Adverse reaction
Frequency of adverse reaction by treatment regimen
Rosiglitazone
monotherapy
Rosiglitazone with
metformin
Rosiglitazone with
metformin and
sulphonylurea
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Common
Common
Common
granulocytopaenia
Common
Metabolism and nutrition disorders
hypercholesterolaemia
1
Common
Common
Common
hypertriglyceridaemia
Common
hyperlipaemia
Common
Common
Common
weight increase
Common
Common
Common
increased appetite
Common
hypoglycaemia
Common
Very common
Nervous system disorders
dizziness*
Common
headache*
Common
Cardiac disorders
cardiac failure
2
Common
Common
cardiac ischaemia
3
*
Common
Common
Common
Gastrointestinal disorders
constipation
Common
Common
Common
Musculoskeletal and connective tissue disorders
bone fractures
4
Common
Common
myalgia*
Common
General disorders and administration site conditions
oedema
Common
Common
Very common
*The frequency category for the background incidence of these events, as taken from placebo group
data from clinical trials, is 'common'.
1
Hypercholesterolaemia was reported in up to 5.3% of patients treated with rosiglitazone
(monotherapy, dual or triple oral therapy). The elevated total cholesterol levels were associated with
an increase in both LDLc and HDLc, but the ratio of total cholesterol: HDLc was unchanged or
improved in long term studies. Overall, these increases were generally mild to moderate and usually
did not require discontinuation of treatment.
2
An increased incidence of heart failure has been observed when rosiglitazone was added to treatment
regimens with a sulphonylurea (either as dual or triple therapy), and appeared higher with 8 mg
rosiglitazone compared to 4 mg rosiglitazone (total daily dose). The incidence of heart failure on triple
oral therapy was 1.4% in the main double blind study, compared to 0.4% for metformin plus
sulphonylurea dual therapy. The incidence of heart failure in combination with insulin (rosiglitazone
added to established insulin therapy) was 2.4%, compared to insulin alone, 1.1%.
In a placebo-controlled one-year trial in patients with congestive heart failure NYHA class I-II,
worsening or possible worsening of heart failure occurred in 6.4% of patients treated with
rosiglitazone, compared with 3.5% on placebo.
9
Blood and the lymphatic system disorders
anaemia
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In double-blind clinical trials with rosiglitazone the incidence of elevations of ALT greater than three
times the upper limit of normal was equal to placebo (0.2%) and less than that of the active
comparators (0.5% metformin/sulphonylureas). The incidence of all adverse events relating to liver
and biliary systems was <1.5% in any treatment group and similar to placebo.
Post-marketing data
In addition to the adverse reactions identified from clinical trial data, the adverse reactions presented
in Table 2 have been identified in post approval use of rosiglitazone.
10
3
In a retrospective analysis of data from 42 pooled short-term clinical studies, the overall incidence of
events typically associated with cardiac ischaemia was higher for rosiglitazone containing regimens,
2.00% versus combined active and placebo comparators, 1.53% [hazard ratio (HR) 1.30 (95%
confidence interval (CI) 1.004 - 1.69)]. This risk was increased when rosiglitazone was added to
established insulin and in patients receiving nitrates for known ischaemic heart disease. In an update to
this retrospective analysis that included 10 further studies that met the criteria for inclusion, but were
not available at the time of the original analysis, the overall incidence of events typically associated
with cardiac ischaemia was not statistically different for rosiglitazone containing regimens, 2.21%
versus combined active and placebo comparators, 2.08% [HR 1.098 (95% CI 0.809 - 1.354)]. In a
prospective cardiovascular outcomes study (mean follow-up 5.5 years) the primary endpoint events of
cardiovascular death or hospitalisation were similar between rosiglitazone and active comparators [HR
0.99 (95% CI 0.85 - 1.16)]. Two other long-term prospective randomised controlled clinical trials
(9,620 patients, study duration >3 years in each study), comparing rosiglitazone to some other
approved oral antidiabetic agents or placebo, have not confirmed or excluded the potential risk of
cardiac ischaemia. In their entirety, the available data on the risk of cardiac ischaemia are
inconclusive.
4
Long-term studies show an increased incidence of bone fracture in patients, particularly female
patients, taking rosiglitazone. In a monotherapy study, the incidence in females for rosiglitazone was
9.3% (2.7 patients per 100 patient years) vs 5.1% (1.5 patients per 100 patient years) for metformin or
3.5% (1.3 patients per 100 patient years) for glibenclamide. In another long-term study, there was an
increased incidence of bone fracture for subjects in the combined rosiglitazone group compared to
active control [8.3% vs 5.3%, Risk ratio 1.57 (95% CI 1.26 - 1.97)]. The risk of fracture appeared to
be higher in females relative to control [11.5% vs 6.3%, Risk ratio 1.82 (95% CI 1.37 - 2.41)], than in
males relative to control [5.3% vs 4.3%, Risk ratio 1.23 (95% CI 0.85 - 1.77)]. Additional data are
necessary to determine whether there is an increased risk of fracture in males after a longer period of
follow-up. The majority of the fractures were reported in the upper limbs and distal lower limbs (see
section 4.4).
Table 2. The frequency of adverse reactions identified from post-marketing data with
rosiglitazone
Adverse reaction
Frequency
Metabolism and nutrition disorders
rapid and excessive weight gain
Very rare
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Very rare
Eye disorders
macular oedema
Rare
Cardiac disorders
congestive heart failure/pulmonary oedema
Rare
Hepatobiliary disorders
hepatic dysfunction, primarily evidenced by elevated hepatic enzymes
5
Rare
Skin and subcutaneous tissue disorders
(see Immune system disorders)
angioedema Very rare
skin reactions (e.g. urticaria, pruritis, rash) Very rare
5
Rare cases of elevated liver enzymes and hepatocellular dysfunction have been reported. In very rare
cases, a fatal outcome has been reported.
Metformin
Clinical Trial Data and Post-marketing data
Table 3 presents adverse reactions by system organ class and by frequency category. Frequency
categories are based on information available from metformin Summary of Product Characteristics
available in the EU.
11
Immune system disorders
(see Skin and subcutaneous tissue disorders)
anaphylactic reaction
Table 3. The frequency of metformin adverse reactions identified from clinical trial and post-
marketing data
Adverse reaction
Frequency
Gastrointestinal disorders
gastrointestinal symptoms
6
Very common
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Very rare
vitamin B12 deficiency
7
Very rare
Nervous system disorders
metallic taste
Common
Hepatobiliary disorders
liver function disorders
Very rare
Hepatitis
Very rare
Skin and subcutaneous disorders
urticaria Very rare
erythema Very rare
pruritis Very rare
6
Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite
occur most frequently during initiation of therapy and resolve spontaneously in most cases.
7
Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption
which may very rarely result in clinically significant vitamin B12 deficiency (e.g. megaloblastic
anaemia).
No data are available with regard to overdose of AVANDAMET.
Limited data are available with regard to overdose of rosiglitazone in humans. In clinical studies in
volunteers rosiglitazone has been administered at single oral doses of up to 20 mg and was well
tolerated.
A large overdose of metformin (or coexisting risks of lactic acidosis) may lead to lactic acidosis which
is a medical emergency and must be treated in hospital.
In the event of an overdose, it is recommended that appropriate supportive treatment is initiated as
dictated by the patient's clinical status. The most effective method to remove lactate and metformin is
haemodialysis, however rosiglitazone is highly protein bound and is not cleared by haemodialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Combinations of oral blood glucose lowering medicinal products, ATC
code: A10BD03
AVANDAMET combines two antihyperglycaemic agents with complimentary mechanisms of action
to improve glycaemic control in patients with type 2 diabetes: rosiglitazone maleate, a member of the
12
Metabolism and nutrition disorders
lactic acidosis
thiazolidinedione class and metformin hydrochloride, a member of the biguanide class.
Thiazolidinediones act primarily by reducing insulin resistance and biguanides act primarily by
decreasing endogenous hepatic glucose production.
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The antihyperglycaemic activity of rosiglitazone has been demonstrated in a number of animal models
of type 2 diabetes. In addition, rosiglitazone preserved ß-cell function as shown by increased
pancreatic islet mass and insulin content and prevented the development of overt hyperglycaemia in
animal models of type 2 diabetes. Rosiglitazone
did not stimulate pancreatic insulin secretion or
induce hypoglycaemia in rats and mice. The major metabolite (a para-hydroxy-sulphate) with high
affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in
obese mice. The clinical relevance of this observation has not been fully elucidated.
In clinical trials, the glucose lowering effects observed with rosiglitazone are gradual in onset with
near maximal reductions in fasting plasma glucose (FPG) evident following approximately 8 weeks of
therapy. The improved glycaemic control is associated with reductions in both fasting and post-
prandial glucose.
Rosiglitazone was associated with increases in weight. In mechanistic studies, the weight increase was
predominantly shown to be due to increased subcutaneous fat with decreased visceral and intra-hepatic
fat.
Consistent with the mechanism of action, rosiglitazone in combination with metformin reduced insulin
resistance and improved pancreatic ß-cell function. Improved glycaemic control was also associated
with significant decreases in free fatty acids. As a consequence of different but complementary
mechanisms of action, combination therapy of rosiglitazone
with
metformin resulted in additive
effects on glycaemic control in type 2 diabetic patients.
In studies with a maximal duration of three years, rosiglitazone given once or twice daily in dual oral
therapy with metformin produced a sustained improvement in glycaemic control (FPG and HbA1c). A
more pronounced glucose-lowering effect was observed in obese patients. An outcome study has not
been completed with rosiglitazone, therefore the long-term benefits associated with improved
glycaemic control of rosiglitazone have not been demonstrated.
An active controlled clinical trial (rosiglitazone up to 8 mg daily or metformin up to 2,000 mg daily)
of 24 weeks duration was performed in 197 children (10-17 years of age) with type 2 diabetes.
Improvement in HbA1c from baseline achieved statistical significance only in the metformin group.
Rosiglitazone failed to demonstrate non-inferiority to metformin. Following rosiglitazone treatment,
there were no new safety concerns noted in children compared to adult patients with type 2 diabetes
mellitus. No long-term efficacy and safety data are available in paediatric patients.
ADOPT (A Diabetes Outcome Progression Trial) was a multicentre, double-blind, controlled trial with
a treatment duration of 4-6 years (median duration of 4 years), in which rosiglitazone at doses of 4 to
8 mg/day was compared to metformin (500 mg to 2000 mg/day) and glibenclamide (2.5 to 15 mg/day)
in 4351 drug naive subjects recently diagnosed (≤3 years) with type 2 diabetes. Rosiglitazone
treatment significantly reduced the risk of reaching monotherapy failure (FPG>10.0 mmol/L) by 63%
relative to glibenclamide (HR 0.37, CI 0.30-0.45) and by 32% relative to metformin (HR 0.68,
CI 0.55-0.85) during the course of the study (up to 72 months of treatment). This translates to a
cumulative incidence of treatment failure of 10.3% for rosiglitazone, 14.8% for metformin and 23.3%
for glibenclamide treated patients. Overall, 43%, 47% and 42% of subjects in the rosiglitazone,
glibenclamide and metformin groups respectively withdrew due to reasons other than monotherapy
failure. The impact of these findings on disease progression or on microvascular or macrovascular
outcomes has not been determined (see section 4.8). In this study, the adverse events observed were
13
Rosiglitazone
Rosiglitazone is a selective agonist at the PPARγ (peroxisome proliferator activated receptor gamma)
nuclear receptor and is a member of the thiazolidinedione class of antihyperglycaemic agents. It
reduces glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver.
consistent with the known adverse event profile for each of the treatments, including continuing
weight gain with rosiglitazone. An additional observation of an increased incidence of bone fractures
was seen in women with rosiglitazone (see sections 4.4 and 4.8).
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Randomised Treatment
†
Mean (SD) dose at end of randomised treatment
Rosiglitazone (either SU or metformin) 6.7 (1.9) mg
Sulphonylurea (background metformin)
Glimepiride* 3.6 (1.8) mg
Metformin (background sulphonylurea) 1995.5 (682.6) mg
*Similar relative effective doses (i.e approximately half maximal dose) for other sulphonylureas
(glibenclamide and glicazide).
† Patients who took designated treatment as randomised in combination with the correct background
treatment and with evaluable data.
No difference in the number of adjudicated primary endpoint events for rosiglitazone (321/2220)
versus active control (323/2227) (HR 0.99, CI 0.85-1.16) was observed, meeting the pre-defined non-
inferiority criterion of 1.20 (non-inferiority p = 0.02). HR and CI for key secondary endpoints were:
all-cause death (HR 0.86, CI 0.68-1.08), MACE (Major Adverse Cardiac Events - cardiovascular
death, acute myocardial infarction, stroke) (HR 0.93, CI 0.74-1.15), cardiovascular death (HR 0.84, CI
0.59-1.18), acute myocardial infarction (HR 1.14, CI 0.80-1.63) and stroke (HR 0.72, CI 0.49-1.06). In
a sub-study at 18 months, add-on rosiglitazone dual therapy was non-inferior to the combination of
sulphonylurea plus metformin for lowering HbA1c. In the final analysis at 5 years, an adjusted mean
reduction from baseline in HbA1c of 0.14% for patients on rosiglitazone added to metformin versus an
increase of 0.17% for patients taking sulphonylurea added to metformin was seen during treatment
with randomised dual-combination therapy (p<0.0001 for treatment difference). An adjusted mean
reduction in HbA1c of 0.24% was seen for patients taking rosiglitazone added to sulphonylurea,
versus a reduction in HbA1c of 0.10% for patients taking metformin added to sulphonylurea,
(p=0.0083 for treatment difference). There was a significant increase in heart failure (fatal and non-
fatal) (HR 2.10, CI 1.35-3.27) and bone fractures (Risk Ratio 1.57, CI 1.26-1.97) in rosiglitazone-
containing treatments compared to active control (see sections 4.4 and 4.8). A total of 564 patients
withdrew from cardiovascular follow-up, which accounted for 12.3% of rosiglitazone patients and
13% of control patients; representing 7.2% of patient-years lost for cardiovascular events follow-up
and 2.0% of patient-years lost for all cause mortality follow-up.
Metformin
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial
plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via three mechanisms:
-
by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis,
-
in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and
utilisation,
-
by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin increases the transport capacity of specific types of membrane glucose transporters
(GLUT-1 and GLUT-4).
14
The RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in
Diabetes) trial was a large (4,447 subjects), open-label, prospective, controlled study (mean follow-up
5.5 years) in which patients with type 2 diabetes inadequately controlled with metformin or
sulphonylurea were randomised to add-on rosiglitazone or metformin or sulphonylurea. The mean
duration of diabetes in these patients was approximately 7 years. The adjudicated primary endpoint
was cardiovascular hospitalisation (which included hospitalisations for heart failure) or cardiovascular
death. Mean doses at the end of randomised treatment are shown in the following table:
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid
metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term
clinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels.
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a significant reduction of the absolute risk of any diabetes-related complication in the metformin
group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years),
p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups
(40.1 events/1,000 patient-years), p=0.0034
-
a significant reduction of the absolute risk of diabetes-related mortality: metformin
7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017
-
a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000
patient-years versus diet alone 20.6 events/1,000 patient-years (p=0.011), and versus the
combined sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years
(p=0.021)
-
a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000
patient-years, diet alone 18 events/1,000 patient-years (p=0.01).
5.2 Pharmacokinetic properties
AVANDAMET
Absorption
No statistically significant difference was observed between the absorption characteristics of
rosiglitazone and metformin from the AVANDAMET tablet and those obtained from rosiglitazone
maleate and metformin hydrochloride tablets, respectively.
Food had no effect on the AUC of rosiglitazone or metformin when AVANDAMET was administered
to healthy volunteers. In the fed state, C
max
was lower (22% rosiglitazone and 15% metformin) and
t
max
delayed (by approximately 1.5 h rosiglitazone and 0.5 h metformin). This food-effect is not
considered clinically significant.
The following statements reflect the pharmacokinetic properties of the individual active substances of
AVANDAMET.
Rosiglitazone
Absorption
Absolute bioavailability of rosiglitazone following both a 4 and an 8 mg oral dose is approximately
99%. Rosiglitazone plasma concentrations peak at around 1 h after dosing. Plasma concentrations are
approximately dose proportional over the therapeutic dose range.
Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), although a
small decrease in C
max
(approximately 20-28%) and a delay in t
max
(approximately 1.75 h) were
observed compared to dosing in the fasting state. These small changes are not clinically significant
and, therefore, it is not necessary to administer rosiglitazone at any particular time in relation to meals.
The absorption of rosiglitazone is not affected by increases in gastric pH.
Distribution
The volume of distribution of rosiglitazone is approximately 14 l in healthy volunteers. Plasma
protein binding of rosiglitazone is high (approximately 99.8%) and is not influenced by concentration
or age. The protein binding of the major metabolite (a para-hydroxy-sulphate) is very high
(> 99.99%).
Metabolism
Metabolism of rosiglitazone is extensive with no parent compound being excreted unchanged. The
major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with
sulphate and glucuronic acid. The contribution of the major metabolite (a para-hydroxy-sulphate) to
15
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood
glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with
metformin after failure of diet alone showed:
-
the overall antihyperglycaemic activity of rosiglitazone has not been fully elucidated in man and it
cannot be ruled out that the metabolite may contribute to the activity. However, this raises no safety
concern regarding target or special populations as hepatic impairment is contraindicated and the phase
III clinical studies included a considerable number of elderly patients and patients with mild to
moderate renal impairment.
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Since there is no significant
in vitro
inhibition of CYP1A2, 2A6, 2C19, 2D6, 2E1, 3A or 4A with
rosiglitazone, there is a low probability of significant metabolism-based interactions with substances
metabolised by these P450 enzymes. Rosiglitazone showed moderate inhibition of CYP2C8
(IC
50
18 µM) and low inhibition of CYP2C9 (IC
50
50 µM)
in vitro
(see section 4.5). An
in vivo
interaction study with warfarin indicated that rosiglitazone does not interact with CYP2C9 substrates
in vivo
.
Elimination
Total plasma clearance of rosiglitazone is around 3 l/h and the terminal elimination half-life of
rosiglitazone is approximately 3-4 h. There is no evidence for unexpected accumulation of
rosiglitazone after once or twice daily dosing. The major route of excretion is the urine with
approximately two-thirds of the dose being eliminated by this route, whereas faecal elimination
accounts for approximately 25% of dose. No intact active substance is excreted in urine or faeces.
The terminal half-life for radioactivity was about 130 h indicating that elimination of metabolites is
very slow. Accumulation of the metabolites in plasma is expected upon repeated dosing, especially
that of the major metabolite (a para-hydroxy-sulphate) for which an 8-fold accumulation is anticipated.
Special populations
Gender: In the pooled population pharmacokinetic analysis, there were no marked differences in the
pharmacokinetics of rosiglitazone between males and females.
Elderly: In the pooled population pharmacokinetic analysis
,
age was not found to influence the
pharmacokinetics of rosiglitazone to any significant extent
.
Children and adolescents: Population pharmacokinetic analysis including 96 paediatric patients aged
10 to 18 years and weighing 35 to 178 kg suggested similar mean CL/F in children and adults.
Individual CL/F in the paediatric population was in the same range as individual adult data. CL/F
seemed to be independent of age, but increased with weight in the paediatric population.
Hepatic impairment: In cirrhotic patients with moderate (Child-Pugh B) hepatic impairment, unbound
C
max
and AUC were 2- and 3-fold higher than in normal subjects. The inter-subject variability was
large, with a 7-fold difference in unbound AUC between patients.
Renal insufficiency: There are no clinically significant differences in the pharmacokinetics of
rosiglitazone in patients with renal impairment or end stage renal disease on chronic dialysis.
Metformin
Absorption
After an oral dose of metformin, t
max
is reached in 2.5 h. Absolute bioavailability of a 500 mg
metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed
fraction recovered in faeces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the
pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing
schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than
1 µg/ml. In controlled clinical trials, maximum metformin plasma levels (C
max
) did not exceed
4 µg/ml, even at maximum doses.
16
In vitro
studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor
contribution by CYP2C9.
Food decreases the extent and slightly delays the absorption of metformin. Following administration
of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min
prolongation of time to peak plasma concentration was observed. The clinical relevance of this
decrease is unknown.
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Metabolism
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination
Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular
filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is
approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to
that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of
metformin in plasma.
5.3 Preclinical safety data
No animal studies have been conducted with the combined products in AVANDAMET. The
following data are findings in studies performed with rosiglitazone or metformin individually.
Rosiglitazone
Undesirable effects observed in animal studies with possible relevance to clinical use were as follows:
An increase in plasma volume accompanied by decrease in red cell parameters and increase in heart
weight. Increases in liver weight, plasma ALT (dog only) and fat tissue were also observed. Similar
effects have been seen with other thiazolidinediones.
In reproductive toxicity studies, administration of rosiglitazone to rats during mid-late gestation was
associated with foetal death and retarded foetal development. In addition, rosiglitazone inhibited
ovarian oestradiol and progesterone synthesis and lowered plasma levels of these hormones resulting
in effects on oestrus/menstrual cycles and fertility (see section 4.4).
In an animal model for familial adenomatous polyposis (FAP), treatment with rosiglitazone at 200
times the pharmacologically active dose increased tumour multiplicity in the colon. The relevance of
this finding is unknown. However, rosiglitazone promoted differentiation and reversal of mutagenic
changes in human colon cancer cells
in vitro
. In addition, rosiglitazone was not genotoxic in a battery
of
in vivo
and
in vitro
genotoxicity studies and there was no evidence of colon tumours in lifetime
studies of rosiglitazone in two rodent species.
Metformin
Non-clinical data for metformin reveal no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to
reproduction.
6.
6.1 List of excipients
Tablet core
:
Sodium starch glycollate
Hypromellose (E464)
Microcrystalline cellulose (E460)
17
Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower
than the plasma peak and appears at approximately the same time. The red blood cells most likely
represent a secondary compartment of distribution. The mean V
d
ranged between 63 – 276 l.
Lactose monohydrate
Povidone (E1201)
Magnesium stearate.
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6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Opaque blisters (PVC/PVdC/aluminium). Packs of 28, 56, 112, 336 (3x112) and 360 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product should be disposed of in accordance with local requirements.
7.
SmithKline Beecham Ltd
980 Great West Road
Brentford, Middlesex
TW8 9GS
United Kingdom
8.
EU/1/03/258/001-003
EU/1/03/258/015
EU/1/03/258/019
9.
Date of first authorisation: 20 October 2003
Date of latest renewal: 20 October 2008
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.ema.europa.eu
18
Film coat:
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol
Iron oxide yellow (E172).
1.
AVANDAMET 2 mg/500 mg film-coated tablets
2.
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Excipients:
Each tablet contains lactose (approximately 11 mg)
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Pale pink film-coated tablets marked "gsk" on one side and "2/500" on the other.
4.
AVANDAMET is indicated in the treatment of type 2 diabetes mellitus patients, particularly
overweight patients:
-
who are unable to achieve sufficient glycaemic control at their maximally tolerated dose of oral
metformin alone.
-
in triple oral therapy with sulphonylurea in patients with insufficient glycaemic control despite
dual oral therapy with their maximally tolerated dose of metformin and a sulphonylurea (see
section 4.4).
The usual starting dose of AVANDAMET is 4 mg/day rosiglitazone plus 2000 mg/day metformin
hydrochloride.
Rosiglitazone can be increased to 8 mg/day after 8 weeks if greater glycaemic control is required. The
maximum recommended daily dose of AVANDAMET is 8 mg rosiglitazone plus 2000 mg metformin
hydrochloride.
The total daily dose of AVANDAMET should be given in two divided doses.
Dose titration with rosiglitazone (added to the optimal dose of metformin) may be considered before
the patient is switched to AVANDAMET.
When clinically appropriate, direct change from metformin monotherapy to AVANDAMET may be
considered.
Taking AVANDAMET with or just after food may reduce gastrointestinal symptoms associated with
metformin.
Triple oral therapy (rosiglitazone, metformin and sulphonylurea) (see section 4.4)
19
Each tablet contains 2 mg of rosiglitazone (as rosiglitazone maleate) and 500 mg of metformin
hydrochloride (corresponding to metformin free base 390 mg).
-
Patients on metformin and sulphonylurea: when appropriate AVANDAMET may be initiated at
4 mg/day rosiglitazone with the dose of metformin substituting that already being taken. An
increase in the rosiglitazone component to 8 mg/day should be undertaken cautiously following
appropriate clinical evaluation to assess the patient's risk of developing adverse reactions
relating to fluid retention (see sections 4.4 and 4.8).
-
Patients established on triple oral therapy: when appropriate, AVANDAMET may substitute
rosiglitazone and metformin doses already being taken.
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Elderly
As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal
function, elderly patients taking AVANDAMET should have their renal function monitored regularly
(see sections 4.3 and 4.4).
Patients with renal impairment
AVANDAMET should not be used in patients with renal failure or renal dysfunction e.g. serum
creatinine levels > 135 μmol/l in males and > 110 μmol/l in females and/or creatinine clearance
< 70 ml/min (see sections 4.3 and 4.4).
Children and adolescents
AVANDAMET is not recommended for use in children and adolescents below 18 years of age as
there are no data available on its safety and efficacy in this age group (see sections 5.1 and 5.2).
AVANDAMET is contraindicated in patients with:
-
hypersensitivity to rosiglitazone, metformin hydrochloride or to any of the excipients
-
cardiac failure or history of cardiac failure (New York Heart Association (NYHA) stages I to
IV)
-
an Acute Coronary Syndrome (unstable angina, NSTEMI and STEMI) (see section 4.4)
-
acute or chronic disease which may cause tissue hypoxia such as:
-
cardiac or respiratory failure
-
recent myocardial infarction
-
shock
-
hepatic impairment
-
acute alcohol intoxication, alcoholism (see section 4.4)
-
diabetic ketoacidosis or diabetic pre-coma
-
renal failure or renal dysfunction e.g. serum creatinine levels > 135 µmol/l in males and
> 110 µmol/l in females and/or creatinine clearance < 70 ml/min (see section 4.4)
-
acute conditions with the potential to alter renal function such as:
-
dehydration
-
severe infection
-
shock
-
intravascular administration of iodinated contrast agents (see section 4.4)
-
lactation.
Lactic acidosis
Lactic acidosis is a very rare, but serious, metabolic complication that can occur due to metformin
accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in
diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be
reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis,
20
Where appropriate, AVANDAMET may be used to substitute concomitant rosiglitazone and
metformin in existing dual or triple oral therapy to simplify treatment.
prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with
hypoxia.
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Renal function
As metformin is excreted by the kidney, serum creatinine concentrations should be determined
regularly:
-
at least once a year in patients with normal renal function
-
at least two to four times a year in patients with serum creatinine levels at the upper limit of
normal and in elderly patients.
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be
exercised in situations where renal function may become impaired, for example when initiating
antihypertensive or diuretic therapy or when starting treatment with an NSAID.
Fluid retention and cardiac failure
Thiazolidinediones can cause fluid retention which may exacerbate or precipitate signs or symptoms
of congestive heart failure. Rosiglitazone can cause dose-dependent fluid retention. The possible
contribution of fluid retention to weight gain should be individually assessed as rapid and excessive
weight gain has been reported very rarely as a sign of fluid retention. All patients, particularly those
receiving concurrent insulin but also sulphonylurea therapy, those at risk for heart failure, and those
with reduced cardiac reserve, should be monitored for signs and symptoms of adverse reactions
relating to fluid retention, including weight gain and heart failure. AVANDAMET must be
discontinued if any deterioration in cardiac status occurs.
The use of AVANDAMET in combination with a sulphonylurea or insulin may be associated with
increased risks of fluid retention and heart failure (see section 4.8). The decision to initiate
AVANDAMET in combination with a sulphonylurea should include consideration of alternative
therapies. Increased monitoring of the patient is recommended if AVANDAMET is used in
combination particularly with insulin but also with a sulphonylurea.
Heart failure was also reported more frequently in patients with a history of heart failure; oedema and
heart failure was also reported more frequently in elderly patients and in patients with mild or
moderate renal failure. Caution should be exercised in patients over 75 years because of the limited
experience in this patient group. Since NSAIDs, insulin and rosiglitazone are all associated with fluid
retention, concomitant administration may increase the risk of oedema.
Combination with insulin
An increased incidence of cardiac failure has been observed in clinical trials when rosiglitazone is
used in combination with insulin. Insulin and rosiglitazone are both associated with fluid retention,
concomitant administration may increase the risk of oedema and could increase the risk of ischaemic
heart disease. Insulin should only be added to established rosiglitazone therapy in exceptional cases
and under close supervision.
Myocardial Ischaemia
A retrospective analysis of data from 42 pooled short-term clinical studies indicated that treatment
with rosiglitazone may be associated with an increased risk of myocardial ischaemic events. However,
in their entirety the available data on the risk of cardiac ischaemia are inconclusive (see section 4.8).
There are limited clinical trial data in patients with ischaemic heart disease and/or peripheral arterial
disease. Therefore, as a precaution, the use of rosiglitazone is not recommended in these patients,
particularly those with myocardial ischaemic symptoms.
21
Diagnosis:
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by
coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l
and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment
with the medicinal product should be discontinued and the patient hospitalised immediately (see
section 4.9).
Acute Coronary Syndrome (ACS)
Patients experiencing an ACS have not been studied in rosiglitazone controlled clinical trials. In view
of the potential for development of heart failure in these patients, rosiglitazone should therefore not be
initiated in patients having an acute coronary event and it should be discontinued during the acute
phase (see section 4.3).
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Eye disorders
Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual
acuity have been reported with thiazolidinediones, including rosiglitazone. Many of these patients
reported concurrent peripheral oedema. It is unclear whether or not there is a direct association
between rosiglitazone and macular oedema but prescribers should be alert to the possibility of macular
oedema if patients report disturbances in visual acuity and appropriate ophthalmologic referral should
be considered.
Weight gain
In clinical trials with rosiglitazone there was evidence of dose-related weight gain, which was greater
when used in combination with insulin. Therefore weight should be closely monitored, given that it
may be attributable to fluid retention, which may be associated with cardiac failure.
Anaemia
Rosiglitazone treatment is associated with a dose-related reduction of haemoglobin levels. In patients
with low haemoglobin levels before initiating therapy, there is an increased risk of anaemia during
treatment with AVANDAMET.
Hypoglycaemia
Patients receiving AVANDAMET in combination with a sulphonylurea or insulin may be at risk for
dose-related hypoglycaemia. Increased monitoring of the patient and a reduction in the dose of the
concomitant agent may be necessary.
Surgery
As AVANDAMET contains metformin hydrochloride, the treatment should be discontinued 48 hours
before elective surgery with general anaesthesia and should not usually be resumed earlier than 48
hours afterwards.
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast agents in radiological studies can lead to renal
failure. Therefore, due to the metformin active substance, AVANDAMET should be discontinued
prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal
function has been re-evaluated and found to be normal (see section 4.5).
Bone disorders
22
Monitoring of liver function
There have been rare reports of hepatocellular dysfunction during post-marketing experience with
rosiglitazone (see section 4.8). There is limited experience with rosiglitazone in patients with elevated
liver enzymes (ALT > 2.5 times the upper limit of normal). Therefore, liver enzymes should be
checked prior to the initiation of therapy with AVANDAMET in all patients and periodically
thereafter based on clinical judgement. Therapy with AVANDAMET should not be initiated in
patients with increased baseline liver enzyme levels (ALT > 2.5 times the upper limit of normal) or
with any other evidence of liver disease. If ALT levels are increased to > 3 times the upper limit of
normal during AVANDAMET therapy, liver enzyme levels should be reassessed as soon as possible.
If ALT levels remain > 3 times the upper limit of normal, therapy 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 AVANDAMET should be guided by clinical
judgement pending laboratory evaluations. If jaundice is observed, therapy should be discontinued.
Long-term studies show an increased incidence of bone fractures in patients, particularly female
patients, taking rosiglitazone (see section 4.8). The majority of the fractures have occurred in the upper
limbs and distal lower limbs. In females, this increased incidence was noted after the first year of
treatment and persisted during long-term treatment. The risk of fracture should be considered in the
care of patients, especially female patients, treated with rosiglitazone.
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AVANDAMET should be used with caution during concomitant administration of CYP2C8 inhibitors
(e.g. gemfibrozil) or inducers (e.g. rifampicin), due to the effect on rosiglitazone pharmacokinetics
(see section 4.5). Furthermore, AVANDAMET should be used with caution during concomitant
administration of cationic medicinal products that are eliminated by renal tubular secretion (e.g.
cimetidine) due to the effect on metformin pharmacokinetics (see section 4.5). Glycaemic control
should be monitored closely. AVANDAMET dose adjustment within the recommended posology or
changes in diabetic treatment should be considered.
All patients should continue their diet with regular distribution of carbohydrate intake during the day.
Overweight patients should continue their energy-restricted diet.
The usual laboratory tests for diabetes monitoring should be performed regularly.
AVANDAMET tablets contain lactose and therefore should not be administered to patients with rare
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption.
There have been no formal interaction studies for AVANDAMET, however the concomitant use of the
active substances in patients in clinical studies and in widespread clinical use has not resulted in any
unexpected interactions. The following statements reflect the information available on the individual
active substances (rosiglitazone and metformin).
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of
fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of
AVANDAMET (see section 4.4). Avoid consumption of alcohol and medicinal products containing
alcohol.
Cationic medicinal products that are eliminated by renal tubular secretion (e.g. cimetidine) may
interact with metformin by competing for common renal tubular transport systems. A study conducted
in seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily,
increased metformin systemic exposure (AUC) by 50% and C
max
by 81%. Therefore, close monitoring
of glycaemic control, dose adjustment within the recommended posology and changes in diabetic
treatment should be considered when cationic medicinal products that are eliminated by renal tubular
secretion are co-administered (see section 4.4).
In vitro
studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with
CYP2C9 as only a minor pathway.
Co-administration of rosiglitazone with gemfibrozil (an inhibitor of CYP2C8) resulted in a twofold
increase in rosiglitazone plasma concentrations. Since there is a potential for an increase in the risk of
dose-related adverse reactions, a decrease in rosiglitazone dose may be needed. Close monitoring of
glycaemic control should be considered (see section 4.4).
23
Other precautions
Premenopausal women have received rosiglitazone during clinical studies. Although hormonal
imbalance has been seen in preclinical studies (see section 5.3), no significant undesirable effects
associated with menstrual disorders have been observed. As a consequence of improving insulin
sensitivity, resumption of ovulation may occur in patients who are anovulatory due to insulin
resistance. Patients should be aware of the risk of pregnancy (see section 4.6).
Co-administration of rosiglitazone with rifampicin (an inducer of CYP2C8) resulted in a 66% decrease
in rosiglitazone plasma concentrations. It cannot be excluded that other inducers (e.g. phenytoin,
carbamazepine, phenobarbital, St John’s wort) may also affect rosiglitazone exposure. The
rosiglitazone dose may need to be increased. Close monitoring of glycaemic control should be
considered (see section 4.4).
Clinically significant interactions with CYP2C9 substrates or inhibitors are not anticipated.
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No clinically relevant interactions with digoxin, the CYP2C9 substrate warfarin, the CYP3A4
substrates nifedipine, ethinylestradiol or norethindrone were observed after co-administration with
rosiglitazone.
Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in
metformin accumulation and a risk of lactic acidosis. Metformin should be discontinued prior to, or at
the time of the test and not reinstituted until 48 hours afterwards and only after renal function has been
re-evaluated and found to be normal.
Combination requiring precautions for use
Glucocorticoids (given by systemic and local routes) beta-2-agonists, and diuretics have intrinsic
hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring
performed, especially at the beginning of treatment. If necessary, the dosage of the
antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal
product and on its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. If necessary, the dosage of the
antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal
product and on its discontinuation.
For AVANDAMET no preclinical or clinical data on exposed pregnancies or lactation are available.
Rosiglitazone has been reported to cross the human placenta and to be detectable in foetal tissues.
There are no adequate data from the use of rosiglitazone in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Therefore, AVANDAMET should not be used during pregnancy. If a patient wishes to become
pregnant or if pregnancy occurs, treatment with AVANDAMET should be discontinued unless the
expected benefit to the mother outweighs the potential risk to the foetus.
Both rosiglitazone and metformin have been detected in the milk of experimental animals. It is not
known whether breast-feeding will lead to exposure of the infant to the medicinal product.
AVANDAMET must therefore not be used in women who are breast-feeding (see section 4.3).
AVANDAMET has no or negligible influence on the ability to drive and use machines.
Adverse reactions are presented below for each of the component parts of AVANDAMET. An adverse
reaction is only presented for the fixed dose combination if it has not been seen in one of the
component parts of AVANDAMET or if it occurred at a higher frequency than that listed for a
component part.
24
Concomitant administration of rosiglitazone with the oral antihyperglycaemic agents glibenclamide
and acarbose did not result in any clinically relevant pharmacokinetic interactions.
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AVANDAMET
Data from double-blind studies confirm that the safety profile of concomitant rosiglitazone and
metformin is similar to that of the combined adverse reaction profile for the two medicinal products.
Data with AVANDAMET is also consistent with this combined adverse reaction profile.
Clinical trial data (addition of insulin to established AVANDAMET therapy)
In a single study (n=322) where insulin was added to patients established on AVANDAMET, no new
adverse events were observed in excess of those already defined for either AVANDAMET or
rosiglitazone combination therapies.
However, the risk of both fluid related adverse events and hypoglycaemia are increased when
AVANDAMET is used in combination with insulin.
Rosiglitazone
Clinical trial data
Adverse reactions for each treatment regimen are presented below by system organ class and absolute
frequency. For dose-related adverse reactions the frequency category reflects the higher dose of
rosiglitazone. Frequency categories do not account for other factors including varying study duration,
pre-existing conditions and baseline patient characteristics.
Table 1 lists adverse reactions identified from an overview of clinical trials involving over 5,000
rosiglitazone-treated patients. Within each system organ class, adverse reactions are presented in the
table by decreasing frequency for the rosiglitazone monotherapy treatment regimen. Within each
frequency grouping, adverse reactions are presented in order of decreasing seriousness.
25
Adverse reactions for each treatment regimen are presented below by system organ class and absolute
frequency. For dose-related adverse reactions the frequency category reflects the higher dose of
rosiglitazone. Frequency categories do not account for other factors including varying study duration,
pre-existing conditions and baseline patient characteristics. Adverse reaction frequency categories
assigned based on clinical trial experience may not reflect the frequency of adverse events occurring
during normal clinical practice. Frequencies are defined as: very common (≥1/10), common (≥1/100 to
<1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000) and very rare (<1/10,000
including isolated reports).
Table 1. The frequency of adverse reactions identified from clinical trial data with rosiglitazone
Adverse reaction
Frequency of adverse reaction by treatment regimen
Rosiglitazone
monotherapy
Rosiglitazone with
metformin
Rosiglitazone with
metformin and
sulphonylurea
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Common
Common
Common
granulocytopaenia
Common
Metabolism and nutrition disorders
hypercholesterolaemia
1
Common
Common
Common
hypertriglyceridaemia
Common
Hyperlipaemia
Common
Common
Common
weight increase
Common
Common
Common
increased appetite
Common
Hypoglycaemia
Common
Very common
Nervous system disorders
dizziness*
Common
headache*
Common
Cardiac disorders
cardiac failure
2
Common
Common
cardiac ischaemia
3
*
Common
Common
Common
Gastrointestinal disorders
Constipation
Common
Common
Common
Musculoskeletal and connective tissue disorders
bone fractures
4
Common
Common
myalgia*
Common
General disorders and administration site conditions
Oedema
Common
Common
Very common
*The frequency category for the background incidence of these events, as taken from placebo group
data from clinical trials, is 'common'.
1
Hypercholesterolaemia was reported in up to 5.3% of patients treated with rosiglitazone
(monotherapy, dual or triple oral therapy). The elevated total cholesterol levels were associated with
an increase in both LDLc and HDLc, but the ratio of total cholesterol: HDLc was unchanged or
improved in long term studies. Overall, these increases were generally mild to moderate and usually
did not require discontinuation of treatment.
2
An increased incidence of heart failure has been observed when rosiglitazone was added to treatment
regimens with a sulphonylurea (either as dual or triple therapy), and appeared higher with 8 mg
rosiglitazone compared to 4 mg rosiglitazone (total daily dose). The incidence of heart failure on triple
oral therapy was 1.4% in the main double blind study, compared to 0.4% for metformin plus
sulphonylurea dual therapy. The incidence of heart failure in combination with insulin (rosiglitazone
added to established insulin therapy) was 2.4%, compared to insulin alone, 1.1%.
In a placebo-controlled one-year trial in patients with congestive heart failure NYHA class I-II,
worsening or possible worsening of heart failure occurred in 6.4% of patients treated with
rosiglitazone, compared with 3.5% on placebo.
26
Blood and the lymphatic system disorders
Anaemia
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In double-blind clinical trials with rosiglitazone the incidence of elevations of ALT greater than three
times the upper limit of normal was equal to placebo (0.2%) and less than that of the active
comparators (0.5% metformin/sulphonylureas). The incidence of all adverse events relating to liver
and biliary systems was <1.5% in any treatment group and similar to placebo.
Post-marketing data
In addition to the adverse reactions identified from clinical trial data, the adverse reactions presented
in Table 2 have been identified in post approval use of rosiglitazone.
27
3
In a retrospective analysis of data from 42 pooled short-term clinical studies, the overall incidence of
events typically associated with cardiac ischaemia was higher for rosiglitazone containing regimens,
2.00% versus combined active and placebo comparators, 1.53% [hazard ratio (HR) 1.30 (95%
confidence interval (CI) 1.004 - 1.69)]. This risk was increased when rosiglitazone was added to
established insulin and in patients receiving nitrates for known ischaemic heart disease. In an update to
this retrospective analysis that included 10 further studies that met the criteria for inclusion, but were
not available at the time of the original analysis, the overall incidence of events typically associated
with cardiac ischaemia was not statistically different for rosiglitazone containing regimens, 2.21%
versus combined active and placebo comparators, 2.08% [HR 1.098 (95% CI 0.809 - 1.354)]. In a
prospective cardiovascular outcomes study (mean follow-up 5.5 years) the primary endpoint events of
cardiovascular death or hospitalisation were similar between rosiglitazone and active comparators [HR
0.99 (95% CI 0.85 - 1.16)]. Two other long-term prospective randomised controlled clinical trials
(9,620 patients, study duration >3 years in each study), comparing rosiglitazone to some other
approved oral antidiabetic agents or placebo, have not confirmed or excluded the potential risk of
cardiac ischaemia. In their entirety, the available data on the risk of cardiac ischaemia are
inconclusive.
4
Long-term studies show an increased incidence of bone fracture in patients, particularly female
patients, taking rosiglitazone. In a monotherapy study, the incidence in females for rosiglitazone was
9.3% (2.7 patients per 100 patient years) vs 5.1% (1.5 patients per 100 patient years) for metformin or
3.5% (1.3 patients per 100 patient years) for glibenclamide. In another long-term study, there was an
increased incidence of bone fracture for subjects in the combined rosiglitazone group compared to
active control [8.3% vs 5.3%, Risk ratio 1.57 (95% CI 1.26 - 1.97)]. The risk of fracture appeared to
be higher in females relative to control [11.5% vs 6.3%, Risk ratio 1.82 (95% CI 1.37 - 2.41)], than in
males relative to control [5.3% vs 4.3%, Risk ratio 1.23 (95% CI 0.85 - 1.77)]. Additional data are
necessary to determine whether there is an increased risk of fracture in males after a longer period of
follow-up. The majority of the fractures were reported in the upper limbs and distal lower limbs (see
section 4.4).
Table 2. The frequency of adverse reactions identified from post-marketing data with
rosiglitazone
Adverse reaction
Frequency
Metabolism and nutrition disorders
rapid and excessive weight gain
Very rare
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Very rare
Eye disorders
macular oedema
Rare
Cardiac disorders
congestive heart failure/pulmonary oedema
Rare
Hepatobiliary disorders
hepatic dysfunction, primarily evidenced by elevated hepatic enzymes
5
Rare
Skin and subcutaneous tissue disorders
(see Immune system disorders)
Angioedema Very rare
skin reactions (e.g. urticaria, pruritis, rash) Very rare
5
Rare cases of elevated liver enzymes and hepatocellular dysfunction have been reported. In very rare
cases, a fatal outcome has been reported.
Metformin
Clinical Trial Data and Post-marketing data
Table 3 presents adverse reactions by system organ class and by frequency category. Frequency
categories are based on information available from metformin Summary of Product Characteristics
available in the EU.
28
Immune system disorders
(see Skin and subcutaneous tissue disorders)
anaphylactic reaction
Table 3. The frequency of metformin adverse reactions identified from clinical trial and post-
marketing data
Adverse reaction
Frequency
Gastrointestinal disorders
gastrointestinal symptoms
6
Very common
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Very rare
vitamin B12 deficiency
7
Very rare
Nervous system disorders
metallic taste
Common
Hepatobiliary disorders
liver function disorders
Very rare
Hepatitis
Very rare
Skin and subcutaneous disorders
urticaria Very rare
Erythema Very rare
Pruritis Very rare
6
Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite
occur most frequently during initiation of therapy and resolve spontaneously in most cases.
7
Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption
which may very rarely result in clinically significant vitamin B12 deficiency (e.g. megaloblastic
anaemia).
No data are available with regard to overdose of AVANDAMET.
Limited data are available with regard to overdose of rosiglitazone in humans. In clinical studies in
volunteers rosiglitazone has been administered at single oral doses of up to 20 mg and was well
tolerated.
A large overdose of metformin (or coexisting risks of lactic acidosis) may lead to lactic acidosis which
is a medical emergency and must be treated in hospital.
In the event of an overdose, it is recommended that appropriate supportive treatment is initiated as
dictated by the patient's clinical status. The most effective method to remove lactate and metformin is
haemodialysis, however rosiglitazone is highly protein bound and is not cleared by haemodialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Combinations of oral blood glucose lowering medicinal products, ATC
code: A10BD03
AVANDAMET combines two antihyperglycaemic agents with complimentary mechanisms of action
to improve glycaemic control in patients with type 2 diabetes: rosiglitazone maleate, a member of the
thiazolidinedione class and metformin hydrochloride, a member of the biguanide class.
29
Metabolism and nutrition disorders
lactic acidosis
Thiazolidinediones act primarily by reducing insulin resistance and biguanides act primarily by
decreasing endogenous hepatic glucose production.
Rosiglitazone
Rosiglitazone is a selective agonist at the PPARγ (peroxisome proliferator activated receptor gamma)
nuclear receptor and is a member of the thiazolidinedione class of antihyperglycaemic agents. It
reduces glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver.
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In clinical trials, the glucose lowering effects observed with rosiglitazone are gradual in onset with
near maximal reductions in fasting plasma glucose (FPG) evident following approximately 8 weeks of
therapy. The improved glycaemic control is associated with reductions in both fasting and post-
prandial glucose.
Rosiglitazone was associated with increases in weight. In mechanistic studies, the weight increase was
predominantly shown to be due to increased subcutaneous fat with decreased visceral and intra-hepatic
fat.
Consistent with the mechanism of action, rosiglitazone in combination with metformin reduced insulin
resistance and improved pancreatic ß-cell function. Improved glycaemic control was also associated
with significant decreases in free fatty acids. As a consequence of different but complementary
mechanisms of action, combination therapy of rosiglitazone
with
metformin resulted in additive
effects on glycaemic control in type 2 diabetic patients.
In studies with a maximal duration of three years, rosiglitazone given once or twice daily in dual oral
therapy with metformin produced a sustained improvement in glycaemic control (FPG and HbA1c). A
more pronounced glucose-lowering effect was observed in obese patients. An outcome study has not
been completed with rosiglitazone, therefore the long-term benefits associated with improved
glycaemic control of rosiglitazone have not been demonstrated.
An active controlled clinical trial (rosiglitazone up to 8 mg daily or metformin up to 2,000 mg daily)
of 24 weeks duration was performed in 197 children (10-17 years of age) with type 2 diabetes.
Improvement in HbA1c from baseline achieved statistical significance only in the metformin group.
Rosiglitazone failed to demonstrate non-inferiority to metformin. Following rosiglitazone treatment,
there were no new safety concerns noted in children compared to adult patients with type 2 diabetes
mellitus. No long-term efficacy and safety data are available in paediatric patients.
ADOPT (A Diabetes Outcome Progression Trial) was a multicentre, double-blind, controlled trial with
a treatment duration of 4-6 years (median duration of 4 years), in which rosiglitazone at doses of 4 to
8 mg/day was compared to metformin (500 mg to 2000 mg/day) and glibenclamide (2.5 to 15 mg/day)
in 4351 drug naive subjects recently diagnosed (≤3 years) with type 2 diabetes. Rosiglitazone
treatment significantly reduced the risk of reaching monotherapy failure (FPG>10.0 mmol/L) by 63%
relative to glibenclamide (HR 0.37, CI 0.30-0.45) and by 32% relative to metformin (HR 0.68,
CI 0.55-0.85) during the course of the study (up to 72 months of treatment). This translates to a
cumulative incidence of treatment failure of 10.3% for rosiglitazone, 14.8% for metformin and 23.3%
for glibenclamide treated patients. Overall, 43%, 47% and 42% of subjects in the rosiglitazone,
glibenclamide and metformin groups respectively withdrew due to reasons other than monotherapy
failure. The impact of these findings on disease progression or on microvascular or macrovascular
outcomes has not been determined (see section 4.8). In this study, the adverse events observed were
consistent with the known adverse event profile for each of the treatments, including continuing
30
The antihyperglycaemic activity of rosiglitazone has been demonstrated in a number of animal models
of type 2 diabetes. In addition, rosiglitazone preserved ß-cell function as shown by increased
pancreatic islet mass and insulin content and prevented the development of overt hyperglycaemia in
animal models of type 2 diabetes. Rosiglitazone
did not stimulate pancreatic insulin secretion or
induce hypoglycaemia in rats and mice. The major metabolite (a para-hydroxy-sulphate) with high
affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in
obese mice. The clinical relevance of this observation has not been fully elucidated.
weight gain with rosiglitazone. An additional observation of an increased incidence of bone fractures
was seen in women with rosiglitazone (see sections 4.4 and 4.8).
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Randomised Treatment
†
Mean (SD) dose at end of randomised treatment
Rosiglitazone (either SU or metformin) 6.7 (1.9) mg
Sulphonylurea (background metformin)
Glimepiride* 3.6 (1.8) mg
Metformin (background sulphonylurea) 1995.5 (682.6) mg
*Similar relative effective doses (i.e approximately half maximal dose) for other sulphonylureas
(glibenclamide and glicazide).
† Patients who took designated treatment as randomised in combination with the correct background
treatment and with evaluable data.
No difference in the number of adjudicated primary endpoint events for rosiglitazone (321/2220)
versus active control (323/2227) (HR 0.99, CI 0.85-1.16) was observed, meeting the pre-defined non-
inferiority criterion of 1.20 (non-inferiority p = 0.02). HR and CI for key secondary endpoints were:
all-cause death (HR 0.86, CI 0.68-1.08), MACE (Major Adverse Cardiac Events - cardiovascular
death, acute myocardial infarction, stroke) (HR 0.93, CI 0.74-1.15), cardiovascular death (HR 0.84, CI
0.59-1.18), acute myocardial infarction (HR 1.14, CI 0.80-1.63) and stroke (HR 0.72, CI 0.49-1.06). In
a sub-study at 18 months, add-on rosiglitazone dual therapy was non-inferior to the combination of
sulphonylurea plus metformin for lowering HbA1c. In the final analysis at 5 years, an adjusted mean
reduction from baseline in HbA1c of 0.14% for patients on rosiglitazone added to metformin versus an
increase of 0.17% for patients taking sulphonylurea added to metformin was seen during treatment
with randomised dual-combination therapy (p<0.0001 for treatment difference). An adjusted mean
reduction in HbA1c of 0.24% was seen for patients taking rosiglitazone added to sulphonylurea,
versus a reduction in HbA1c of 0.10% for patients taking metformin added to sulphonylurea,
(p=0.0083 for treatment difference). There was a significant increase in heart failure (fatal and non-
fatal) (HR 2.10, CI 1.35-3.27) and bone fractures (Risk Ratio 1.57, CI 1.26-1.97) in rosiglitazone-
containing treatments compared to active control (see sections 4.4 and 4.8). A total of 564 patients
withdrew from cardiovascular follow-up, which accounted for 12.3% of rosiglitazone patients and
13% of control patients; representing 7.2% of patient-years lost for cardiovascular events follow-up
and 2.0% of patient-years lost for all cause mortality follow-up.
Metformin
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial
plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via three mechanisms:
-
by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis
-
in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and
utilisation
-
by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin increases the transport capacity of specific types of membrane glucose transporters
(GLUT-1 and GLUT-4).
31
The RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in
Diabetes) trial was a large (4,447 subjects), open-label, prospective, controlled study (mean follow-up
5.5 years) in which patients with type 2 diabetes inadequately controlled with metformin or
sulphonylurea were randomised to add-on rosiglitazone or metformin or sulphonylurea. The mean
duration of diabetes in these patients was approximately 7 years. The adjudicated primary endpoint
was cardiovascular hospitalisation (which included hospitalisations for heart failure) or cardiovascular
death. Mean doses at the end of randomised treatment are shown in the following table:
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid
metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term
clinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels.
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a significant reduction of the absolute risk of any diabetes-related complication in the metformin
group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years),
p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups
(40.1 events/1,000 patient-years), p=0.0034
-
a significant reduction of the absolute risk of diabetes-related mortality: metformin
7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017
-
a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000
patient-years versus diet alone 20.6 events/1,000 patient-years (p=0.011), and versus the
combined sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years
(p=0.021)
-
a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000
patient-years, diet alone 18 events/1,000 patient-years (p=0.01).
5.2 Pharmacokinetic properties
AVANDAMET
Absorption
No statistically significant difference was observed between the absorption characteristics of
rosiglitazone and metformin from the AVANDAMET tablet and those obtained from rosiglitazone
maleate and metformin hydrochloride tablets, respectively.
Food had no effect on the AUC of rosiglitazone or metformin when AVANDAMET was administered
to healthy volunteers. In the fed state, C
max
was lower (22% rosiglitazone and 15% metformin) and
t
max
delayed (by approximately 1.5 h rosiglitazone and 0.5 h metformin). This food-effect is not
considered clinically significant.
The following statements reflect the pharmacokinetic properties of the individual active substances of
AVANDAMET.
Rosiglitazone
Absorption
Absolute bioavailability of rosiglitazone following both a 4 and an 8 mg oral dose is approximately
99%. Rosiglitazone plasma concentrations peak at around 1 h after dosing. Plasma concentrations are
approximately dose proportional over the therapeutic dose range.
Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), although a
small decrease in C
max
(approximately 20-28%) and a delay in t
max
(approximately 1.75 h) were
observed compared to dosing in the fasting state. These small changes are not clinically significant
and, therefore, it is not necessary to administer rosiglitazone at any particular time in relation to meals.
The absorption of rosiglitazone is not affected by increases in gastric pH.
Distribution
The volume of distribution of rosiglitazone is approximately 14 l in healthy volunteers. Plasma
protein binding of rosiglitazone is high (approximately 99.8%) and is not influenced by concentration
or age. The protein binding of the major metabolite (a para-hydroxy-sulphate) is very high
(> 99.99%).
Metabolism
Metabolism of rosiglitazone is extensive with no parent compound being excreted unchanged. The
major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with
sulphate and glucuronic acid. The contribution of the major metabolite (a para-hydroxy-sulphate) to
32
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood
glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with
metformin after failure of diet alone showed:
-
the overall antihyperglycaemic activity of rosiglitazone has not been fully elucidated in man and it
cannot be ruled out that the metabolite may contribute to the activity. However, this raises no safety
concern regarding target or special populations as hepatic impairment is contraindicated and the phase
III clinical studies included a considerable number of elderly patients and patients with mild to
moderate renal impairment.
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Since there is no significant
in vitro
inhibition of CYP1A2, 2A6, 2C19, 2D6, 2E1, 3A or 4A with
rosiglitazone, there is a low probability of significant metabolism-based interactions with substances
metabolised by these P450 enzymes. Rosiglitazone showed moderate inhibition of CYP2C8
(IC
50
18 µM) and low inhibition of CYP2C9 (IC
50
50 µM)
in vitro
(see section 4.5). An
in vivo
interaction study with warfarin indicated that rosiglitazone does not interact with CYP2C9 substrates
in vivo
.
Elimination
Total plasma clearance of rosiglitazone is around 3 l/h and the terminal elimination half-life of
rosiglitazone is approximately 3-4 h. There is no evidence for unexpected accumulation of
rosiglitazone after once or twice daily dosing. The major route of excretion is the urine with
approximately two-thirds of the dose being eliminated by this route, whereas faecal elimination
accounts for approximately 25% of dose. No intact active substance is excreted in urine or faeces.
The terminal half-life for radioactivity was about 130 h indicating that elimination of metabolites is
very slow. Accumulation of the metabolites in plasma is expected upon repeated dosing, especially
that of the major metabolite (a para-hydroxy-sulphate) for which an 8-fold accumulation is anticipated.
Special populations
Gender: In the pooled population pharmacokinetic analysis, there were no marked differences in the
pharmacokinetics of rosiglitazone between males and females.
Elderly: In the pooled population pharmacokinetic analysis
,
age was not found to influence the
pharmacokinetics of rosiglitazone to any significant extent
.
Children and adolescents: Population pharmacokinetic analysis including 96 paediatric patients aged
10 to 18 years and weighing 35 to 178 kg suggested similar mean CL/F in children and adults.
Individual CL/F in the paediatric population was in the same range as individual adult data. CL/F
seemed to be independent of age, but increased with weight in the paediatric population.
Hepatic impairment: In cirrhotic patients with moderate (Child-Pugh B) hepatic impairment, unbound
C
max
and AUC were 2- and 3-fold higher than in normal subjects. The inter-subject variability was
large, with a 7-fold difference in unbound AUC between patients.
Renal insufficiency: There are no clinically significant differences in the pharmacokinetics of
rosiglitazone in patients with renal impairment or end stage renal disease on chronic dialysis.
Metformin
Absorption
After an oral dose of metformin, t
max
is reached in 2.5 h. Absolute bioavailability of a 500 mg
metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed
fraction recovered in faeces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the
pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing
schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than
1 µg/ml. In controlled clinical trials, maximum metformin plasma levels (C
max
) did not exceed
4 µg/ml, even at maximum doses.
33
In vitro
studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor
contribution by CYP2C9.
Food decreases the extent and slightly delays the absorption of metformin. Following administration
of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min
prolongation of time to peak plasma concentration was observed. The clinical relevance of this
decrease is unknown.
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Metabolism
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination
Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular
filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is
approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to
that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of
metformin in plasma.
5.3 Preclinical safety data
No animal studies have been conducted with the combined products in AVANDAMET. The
following data are findings in studies performed with rosiglitazone or metformin individually.
Rosiglitazone
Undesirable effects observed in animal studies with possible relevance to clinical use were as follows:
An increase in plasma volume accompanied by decrease in red cell parameters and increase in heart
weight. Increases in liver weight, plasma ALT (dog only) and fat tissue were also observed. Similar
effects have been seen with other thiazolidinediones.
In reproductive toxicity studies, administration of rosiglitazone to rats during mid-late gestation was
associated with foetal death and retarded foetal development. In addition, rosiglitazone inhibited
ovarian oestradiol and progesterone synthesis and lowered plasma levels of these hormones resulting
in effects on oestrus/menstrual cycles and fertility (see section 4.4).
In an animal model for familial adenomatous polyposis (FAP), treatment with rosiglitazone at 200
times the pharmacologically active dose increased tumour multiplicity in the colon. The relevance of
this finding is unknown. However, rosiglitazone promoted differentiation and reversal of mutagenic
changes in human colon cancer cells
in vitro
. In addition, rosiglitazone was not genotoxic in a battery
of
in vivo
and
in vitro
genotoxicity studies and there was no evidence of colon tumours in lifetime
studies of rosiglitazone in two rodent species.
Metformin
Non-clinical data for metformin reveal no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to
reproduction.
6.
6.1 List of excipients
Tablet core
:
Sodium starch glycollate
Hypromellose (E464)
Microcrystalline cellulose (E460)
34
Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower
than the plasma peak and appears at approximately the same time. The red blood cells most likely
represent a secondary compartment of distribution. The mean V
d
ranged between 63 – 276 l.
Lactose monohydrate
Povidone (E1201)
Magnesium stearate.
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6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Opaque blisters (PVC/PVdC/aluminium). Packs of 28, 56, 112, 336 (3x112) and 360 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product should be disposed of in accordance with local requirements.
7.
SmithKline Beecham Ltd
980 Great West Road
Brentford, Middlesex
TW8 9GS
United Kingdom
8.
EU/1/03/258/004-006
EU/1/03/258/016
EU/1/03/258/020
9.
Date of first authorisation: 20 October 2003
Date of latest renewal: 20 October 2008
35
Film coat:
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol
Iron oxide red (E172).
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.ema.europa.eu
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36
1.
AVANDAMET 2 mg/1000 mg film-coated tablets
2.
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Excipients:
Each tablet contains lactose (approximately 11 mg)
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Yellow film-coated tablets marked "gsk" on one side and "2/1000" on the other.
4.
AVANDAMET is indicated in the treatment of type 2 diabetes mellitus patients, particularly
overweight patients:
-
who are unable to achieve sufficient glycaemic control at their maximally tolerated dose of oral
metformin alone.
-
in triple oral therapy with sulphonylurea in patients with insufficient glycaemic control despite
dual oral therapy with their maximally tolerated dose of metformin and a sulphonylurea (see
section 4.4).
For the different dosage regimens, AVANDAMET is available in appropriate strengths
.
The usual starting dose of AVANDAMET is 4 mg/day rosiglitazone plus 2000 mg/day metformin
hydrochloride.
Rosiglitazone can be increased to 8 mg/day after 8 weeks if greater glycaemic control is required. The
maximum recommended daily dose of AVANDAMET is 8 mg rosiglitazone plus 2000 mg metformin
hydrochloride.
The total daily dose of AVANDAMET should be given in two divided doses.
Dose titration with rosiglitazone (added to the optimal dose of metformin) may be considered before
the patient is switched to AVANDAMET.
When clinically appropriate, direct change from metformin monotherapy to AVANDAMET may be
considered.
Taking AVANDAMET with or just after food may reduce gastrointestinal symptoms associated with
metformin.
37
Each tablet contains 2 mg of rosiglitazone (as rosiglitazone maleate) and 1000 mg of metformin
hydrochloride (corresponding to metformin free base 780 mg).
Triple oral therapy (rosiglitazone, metformin and sulphonylurea) (see section 4.4)
-
Patients on metformin and sulphonylurea: when appropriate AVANDAMET may be initiated at
4 mg/day rosiglitazone with the dose of metformin substituting that already being taken. An
increase in the rosiglitazone component to 8 mg/day should be undertaken cautiously following
appropriate clinical evaluation to assess the patient's risk of developing adverse reactions
relating to fluid retention (see sections 4.4 and 4.8).
-
Patients established on triple oral therapy: when appropriate, AVANDAMET may substitute
rosiglitazone and metformin doses already being taken.
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Where appropriate, AVANDAMET may be used to substitute concomitant rosiglitazone and
metformin in existing dual or triple oral therapy to simplify treatment.
Elderly
As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal
function, elderly patients taking AVANDAMET should have their renal function monitored regularly
(see sections 4.3 and 4.4).
Patients with renal impairment
AVANDAMET should not be used in patients with renal failure or renal dysfunction e.g. serum
creatinine levels > 135 μmol/l in males and > 110 μmol/l in females and/or creatinine clearance
< 70 ml/min (see sections 4.3 and 4.4).
Children and adolescents
AVANDAMET is not recommended for use in children and adolescents below 18 years of age as
there are no data available on its safety and efficacy in this age group (see sections 5.1 and 5.2).
AVANDAMET is contraindicated in patients with:
-
cardiac failure or history of cardiac failure (New York Heart Association (NYHA) stages I to
IV)
-
acute or chronic disease which may cause tissue hypoxia such as:
-
cardiac or respiratory failure
-
recent myocardial infarction
-
shock
-
hepatic impairment
-
acute alcohol intoxication, alcoholism (see section 4.4)
-
diabetic ketoacidosis or diabetic pre-coma
-
renal failure or renal dysfunction e.g. serum creatinine levels > 135 µmol/l in males and
> 110 µmol/l in females and/or creatinine clearance < 70 ml/min (see section 4.4)
-
acute conditions with the potential to alter renal function such as:
-
-
severe infection
-
shock
-
intravascular administration of iodinated contrast agents (see section 4.4)
-
lactation.
Lactic acidosis
Lactic acidosis is a very rare, but serious, metabolic complication that can occur due to metformin
accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in
diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be
reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis,
38
-
hypersensitivity to rosiglitazone, metformin hydrochloride or to any of the excipients
-
an Acute Coronary Syndrome (unstable angina, NSTEMI and STEMI) (see section 4.4)
dehydration
prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with
hypoxia.
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Renal function
As metformin is excreted by the kidney, serum creatinine concentrations should be determined
regularly:
-
at least once a year in patients with normal renal function
-
at least two to four times a year in patients with serum creatinine levels at the upper limit of
normal and in elderly patients.
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be
exercised in situations where renal function may become impaired, for example when initiating
antihypertensive or diuretic therapy or when starting treatment with an NSAID.
Fluid retention and cardiac failure
Thiazolidinediones can cause fluid retention which may exacerbate or precipitate signs or symptoms
of congestive heart failure. Rosiglitazone can cause dose-dependent fluid retention. The possible
contribution of fluid retention to weight gain should be individually assessed as rapid and excessive
weight gain has been reported very rarely as a sign of fluid retention. All patients, particularly those
receiving concurrent insulin but also sulphonylurea therapy, those at risk for heart failure, and those
with reduced cardiac reserve, should be monitored for signs and symptoms of adverse reactions
relating to fluid retention, including weight gain and heart failure. AVANDAMET must be
discontinued if any deterioration in cardiac status occurs.
The use of AVANDAMET in combination with a sulphonylurea or insulin may be associated with
increased risks of fluid retention and heart failure (see section 4.8). The decision to initiate
AVANDAMET in combination with a sulphonylurea should include consideration of alternative
therapies. Increased monitoring of the patient is recommended if AVANDAMET is used in
combination particularly with insulin but also with a sulphonylurea.
Heart failure was also reported more frequently in patients with a history of heart failure; oedema and
heart failure was also reported more frequently in elderly patients and in patients with mild or
moderate renal failure. Caution should be exercised in patients over 75 years because of the limited
experience in this patient group. Since NSAIDs, insulin and rosiglitazone are all associated with fluid
retention, concomitant administration may increase the risk of oedema.
Combination with insulin
An increased incidence of cardiac failure has been observed in clinical trials when rosiglitazone is
used in combination with insulin. Insulin and rosiglitazone are both associated with fluid retention,
concomitant administration may increase the risk of oedema and could increase the risk of ischaemic
heart disease. Insulin should only be added to established rosiglitazone therapy in exceptional cases
and under close supervision.
Myocardial Ischaemia
A retrospective analysis of data from 42 pooled short-term clinical studies indicated that treatment
with rosiglitazone may be associated with an increased risk of myocardial ischaemic events. However,
in their entirety the available data on the risk of cardiac ischaemia are inconclusive (see section 4.8).
There are limited clinical trial data in patients with ischaemic heart disease and/or peripheral arterial
disease. Therefore, as a precaution, the use of rosiglitazone is not recommended in these patients,
particularly those with myocardial ischaemic symptoms.
39
Diagnosis:
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by
coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l
and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment
with the medicinal product should be discontinued and the patient hospitalised immediately (see
section 4.9).
Acute Coronary Syndrome (ACS)
Patients experiencing an ACS have not been studied in rosiglitazone controlled clinical trials. In view
of the potential for development of heart failure in these patients, rosiglitazone should therefore not be
initiated in patients having an acute coronary event and it should be discontinued during the acute
phase (see section 4.3).
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Eye disorders
Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual
acuity have been reported with thiazolidinediones, including rosiglitazone. Many of these patients
reported concurrent peripheral oedema. It is unclear whether or not there is a direct association
between rosiglitazone and macular oedema but prescribers should be alert to the possibility of macular
oedema if patients report disturbances in visual acuity and appropriate ophthalmologic referral should
be considered.
Weight gain
In clinical trials with rosiglitazone there was evidence of dose-related weight gain, which was greater
when used in combination with insulin. Therefore weight should be closely monitored, given that it
may be attributable to fluid retention, which may be associated with cardiac failure.
Anaemia
Rosiglitazone treatment is associated with a dose-related reduction of haemoglobin levels. In patients
with low haemoglobin levels before initiating therapy, there is an increased risk of anaemia during
treatment with AVANDAMET.
Hypoglycaemia
Patients receiving AVANDAMET in combination with a sulphonylurea or insulin may be at risk for
dose-related hypoglycaemia. Increased monitoring of the patient and a reduction in the dose of the
concomitant agent may be necessary.
Surgery
As AVANDAMET contains metformin hydrochloride, the treatment should be discontinued 48 hours
before elective surgery with general anaesthesia and should not usually be resumed earlier than 48
hours afterwards.
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast agents in radiological studies can lead to renal
failure. Therefore, due to the metformin active substance, AVANDAMET should be discontinued
prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal
function has been re-evaluated and found to be normal (see section 4.5).
Bone disorders
40
Monitoring of liver function
There have been rare reports of hepatocellular dysfunction during post-marketing experience with
rosiglitazone (see section 4.8). There is limited experience with rosiglitazone in patients with elevated
liver enzymes (ALT > 2.5 times the upper limit of normal). Therefore, liver enzymes should be
checked prior to the initiation of therapy with AVANDAMET in all patients and periodically
thereafter based on clinical judgement. Therapy with AVANDAMET should not be initiated in
patients with increased baseline liver enzyme levels (ALT > 2.5 times the upper limit of normal) or
with any other evidence of liver disease. If ALT levels are increased to > 3 times the upper limit of
normal during AVANDAMET therapy, liver enzyme levels should be reassessed as soon as possible.
If ALT levels remain > 3 times the upper limit of normal, therapy 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 AVANDAMET should be guided by clinical
judgement pending laboratory evaluations. If jaundice is observed, therapy should be discontinued.
Long-term studies show an increased incidence of bone fractures in patients, particularly female
patients, taking rosiglitazone (see section 4.8). The majority of the fractures have occurred in the upper
limbs and distal lower limbs. In females, this increased incidence was noted after the first year of
treatment and persisted during long-term treatment. The risk of fracture should be considered in the
care of patients, especially female patients, treated with rosiglitazone.
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AVANDAMET should be used with caution during concomitant administration of CYP2C8 inhibitors
(e.g. gemfibrozil) or inducers (e.g. rifampicin), due to the effect on rosiglitazone pharmacokinetics
(see section 4.5). Furthermore, AVANDAMET should be used with caution during concomitant
administration of cationic medicinal products that are eliminated by renal tubular secretion (e.g.
cimetidine) due to the effect on metformin pharmacokinetics (see section 4.5). Glycaemic control
should be monitored closely. AVANDAMET dose adjustment within the recommended posology or
changes in diabetic treatment should be considered.
All patients should continue their diet with regular distribution of carbohydrate intake during the day.
Overweight patients should continue their energy-restricted diet.
The usual laboratory tests for diabetes monitoring should be performed regularly.
AVANDAMET tablets contain lactose and therefore should not be administered to patients with rare
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption.
There have been no formal interaction studies for AVANDAMET, however the concomitant use of the
active substances in patients in clinical studies and in widespread clinical use has not resulted in any
unexpected interactions. The following statements reflect the information available on the individual
active substances (rosiglitazone and metformin).
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of
fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of
AVANDAMET (see section 4.4). Avoid consumption of alcohol and medicinal products containing
alcohol.
Cationic medicinal products that are eliminated by renal tubular secretion (e.g. cimetidine) may
interact with metformin by competing for common renal tubular transport systems. A study conducted
in seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily,
increased metformin systemic exposure (AUC) by 50% and C
max
by 81%. Therefore, close monitoring
of glycaemic control, dose adjustment within the recommended posology and changes in diabetic
treatment should be considered when cationic medicinal products that are eliminated by renal tubular
secretion are co-administered (see section 4.4).
In vitro
studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with
CYP2C9 as only a minor pathway.
Co-administration of rosiglitazone with gemfibrozil (an inhibitor of CYP2C8) resulted in a twofold
increase in rosiglitazone plasma concentrations. Since there is a potential for an increase in the risk of
dose-related adverse reactions, a decrease in rosiglitazone dose may be needed. Close monitoring of
glycaemic control should be considered (see section 4.4).
41
Other precautions
Premenopausal women have received rosiglitazone during clinical studies. Although hormonal
imbalance has been seen in preclinical studies (see section 5.3), no significant undesirable effects
associated with menstrual disorders have been observed. As a consequence of improving insulin
sensitivity, resumption of ovulation may occur in patients who are anovulatory due to insulin
resistance. Patients should be aware of the risk of pregnancy (see section 4.6).
Co-administration of rosiglitazone with rifampicin (an inducer of CYP2C8) resulted in a 66% decrease
in rosiglitazone plasma concentrations. It cannot be excluded that other inducers (e.g. phenytoin,
carbamazepine, phenobarbital, St John’s wort) may also affect rosiglitazone exposure. The
rosiglitazone dose may need to be increased. Close monitoring of glycaemic control should be
considered (see section 4.4).
Clinically significant interactions with CYP2C9 substrates or inhibitors are not anticipated.
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No clinically relevant interactions with digoxin, the CYP2C9 substrate warfarin, the CYP3A4
substrates nifedipine, ethinylestradiol or norethindrone were observed after co-administration with
rosiglitazone.
Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in
metformin accumulation and a risk of lactic acidosis. Metformin should be discontinued prior to, or at
the time of the test and not reinstituted until 48 hours afterwards and only after renal function has been
re-evaluated and found to be normal.
Combination requiring precautions for use
Glucocorticoids (given by systemic and local routes) beta-2-agonists, and diuretics have intrinsic
hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring
performed, especially at the beginning of treatment. If necessary, the dosage of the
antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal
product and on its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. If necessary, the dosage of the
antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal
product and on its discontinuation.
For AVANDAMET no preclinical or clinical data on exposed pregnancies or lactation are available.
Rosiglitazone has been reported to cross the human placenta and to be detectable in foetal tissues.
There are no adequate data from the use of rosiglitazone in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Therefore, AVANDAMET should not be used during pregnancy. If a patient wishes to become
pregnant or if pregnancy occurs, treatment with AVANDAMET should be discontinued unless the
expected benefit to the mother outweighs the potential risk to the foetus.
Both rosiglitazone and metformin have been detected in the milk of experimental animals. It is not
known whether breast-feeding will lead to exposure of the infant to the medicinal product.
AVANDAMET must therefore not be used in women who are breast-feeding (see section 4.3).
AVANDAMET has no or negligible influence on the ability to drive and use machines.
Adverse reactions are presented below for each of the component parts of AVANDAMET. An adverse
reaction is only presented for the fixed dose combination if it has not been seen in one of the
component parts of AVANDAMET or if it occurred at a higher frequency than that listed for a
component part.
42
Concomitant administration of rosiglitazone with the oral antihyperglycaemic agents glibenclamide
and acarbose did not result in any clinically relevant pharmacokinetic interactions.
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AVANDAMET
Data from double-blind studies confirm that the safety profile of concomitant rosiglitazone and
metformin is similar to that of the combined adverse reaction profile for the two medicinal products.
Data with AVANDAMET is also consistent with this combined adverse reaction profile.
Clinical trial data (addition of insulin to established AVANDAMET therapy)
In a single study (n=322) where insulin was added to patients established on AVANDAMET, no new
adverse events were observed in excess of those already defined for either AVANDAMET or
rosiglitazone combination therapies.
However, the risk of both fluid related adverse events and hypoglycaemia are increased when
AVANDAMET is used in combination with insulin.
Rosiglitazone
Clinical trial data
Adverse reactions for each treatment regimen are presented below by system organ class and absolute
frequency. For dose-related adverse reactions the frequency category reflects the higher dose of
rosiglitazone. Frequency categories do not account for other factors including varying study duration,
pre-existing conditions and baseline patient characteristics.
Table 1 lists adverse reactions identified from an overview of clinical trials involving over 5,000
rosiglitazone-treated patients. Within each system organ class, adverse reactions are presented in the
table by decreasing frequency for the rosiglitazone monotherapy treatment regimen. Within each
frequency grouping, adverse reactions are presented in order of decreasing seriousness.
43
Adverse reactions for each treatment regimen are presented below by system organ class and absolute
frequency. For dose-related adverse reactions the frequency category reflects the higher dose of
rosiglitazone. Frequency categories do not account for other factors including varying study duration,
pre-existing conditions and baseline patient characteristics. Adverse reaction frequency categories
assigned based on clinical trial experience may not reflect the frequency of adverse events occurring
during normal clinical practice. Frequencies are defined as: very common (≥1/10), common (≥1/100 to
<1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000) and very rare (<1/10,000
including isolated reports).
Table 1. The frequency of adverse reactions identified from clinical trial data with rosiglitazone
Adverse reaction
Frequency of adverse reaction by treatment regimen
Rosiglitazone
monotherapy
Rosiglitazone with
metformin
Rosiglitazone with
metformin and
sulphonylurea
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Common
Common
Common
granulocytopaenia
Common
Metabolism and nutrition disorders
hypercholesterolaemia
1
Common
Common
Common
hypertriglyceridaemia
Common
hyperlipaemia
Common
Common
Common
weight increase
Common
Common
Common
increased appetite
Common
hypoglycaemia
Common
Very common
Nervous system disorders
dizziness*
Common
headache*
Common
Cardiac disorders
cardiac failure
2
Common
Common
cardiac ischaemia
3
*
Common
Common
Common
Gastrointestinal disorders
constipation
Common
Common
Common
Musculoskeletal and connective tissue disorders
bone fractures
4
Common
Common
myalgia*
Common
General disorders and administration site conditions
oedema
Common
Common
Very common
*The frequency category for the background incidence of these events, as taken from placebo group
data from clinical trials, is 'common'.
1
Hypercholesterolaemia was reported in up to 5.3% of patients treated with rosiglitazone
(monotherapy, dual or triple oral therapy). The elevated total cholesterol levels were associated with
an increase in both LDLc and HDLc, but the ratio of total cholesterol: HDLc was unchanged or
improved in long term studies. Overall, these increases were generally mild to moderate and usually
did not require discontinuation of treatment.
2
An increased incidence of heart failure has been observed when rosiglitazone was added to treatment
regimens with a sulphonylurea (either as dual or triple therapy), and appeared higher with 8 mg
rosiglitazone compared to 4 mg rosiglitazone (total daily dose). The incidence of heart failure on
triple oral therapy was 1.4% in the main double blind study, compared to 0.4% for metformin plus
sulphonylurea dual therapy. The incidence of heart failure in combination with insulin (rosiglitazone
added to established insulin therapy) was 2.4%, compared to insulin alone, 1.1%.
44
Blood and the lymphatic system disorders
anaemia
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In double-blind clinical trials with rosiglitazone the incidence of elevations of ALT greater than three
times the upper limit of normal was equal to placebo (0.2%) and less than that of the active
comparators (0.5% metformin/sulphonylureas). The incidence of all adverse events relating to liver
and biliary systems was <1.5% in any treatment group and similar to placebo.
Post-marketing data
In addition to the adverse reactions identified from clinical trial data, the adverse reactions presented
in Table 2 have been identified in post approval use of rosiglitazone.
45
In a placebo-controlled one-year trial in patients with congestive heart failure NYHA class I-II,
worsening or possible worsening of heart failure occurred in 6.4% of patients treated with
rosiglitazone, compared with 3.5% on placebo.
3
In a retrospective analysis of data from 42 pooled short-term clinical studies, the overall incidence of
events typically associated with cardiac ischaemia was higher for rosiglitazone containing regimens,
2.00% versus combined active and placebo comparators, 1.53% [hazard ratio (HR) 1.30 (95%
confidence interval (CI) 1.004 - 1.69)]. This risk was increased when rosiglitazone was added to
established insulin and in patients receiving nitrates for known ischaemic heart disease. In an update to
this retrospective analysis that included 10 further studies that met the criteria for inclusion, but were
not available at the time of the original analysis, the overall incidence of events typically associated
with cardiac ischaemia was not statistically different for rosiglitazone containing regimens, 2.21%
versus combined active and placebo comparators, 2.08% [HR 1.098 (95% CI 0.809 - 1.354)]. In a
prospective cardiovascular outcomes study (mean follow-up 5.5 years) the primary endpoint events of
cardiovascular death or hospitalisation were similar between rosiglitazone and active comparators [HR
0.99 (95% CI 0.85 - 1.16)]. Two other long-term prospective randomised controlled clinical trials
(9,620 patients, study duration >3 years in each study), comparing rosiglitazone to some other
approved oral antidiabetic agents or placebo, have not confirmed or excluded the potential risk of
cardiac ischaemia. In their entirety, the available data on the risk of cardiac ischaemia are
inconclusive.
4
Long-term studies show an increased incidence of bone fracture in patients, particularly female
patients, taking rosiglitazone. In a monotherapy study, the incidence in females for rosiglitazone was
9.3% (2.7 patients per 100 patient years) vs 5.1% (1.5 patients per 100 patient years) for metformin or
3.5% (1.3 patients per 100 patient years) for glibenclamide. In another long-term study, there was an
increased incidence of bone fracture for subjects in the combined rosiglitazone group compared to
active control [8.3% vs 5.3%, Risk ratio 1.57 (95% CI 1.26 - 1.97)]. The risk of fracture appeared to
be higher in females relative to control [11.5% vs 6.3%, Risk ratio 1.82 (95% CI 1.37 - 2.41)], than in
males relative to control [5.3% vs 4.3%, Risk ratio 1.23 (95% CI 0.85 - 1.77)]. Additional data are
necessary to determine whether there is an increased risk of fracture in males after a longer period of
follow-up. The majority of the fractures were reported in the upper limbs and distal lower limbs (see
section 4.4).
Table 2. The frequency of adverse reactions identified from post-marketing data with
rosiglitazone
Adverse reaction
Frequency
Metabolism and nutrition disorders
rapid and excessive weight gain
Very rare
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Very rare
Eye disorders
macular oedema
Rare
Cardiac disorders
congestive heart failure/pulmonary oedema
Rare
Hepatobiliary disorders
hepatic dysfunction, primarily evidenced by elevated hepatic enzymes
5
Rare
Skin and subcutaneous tissue disorders
(see Immune system disorders)
angioedema Very rare
skin reactions (e.g. urticaria, pruritis, rash) Very rare
5
Rare cases of elevated liver enzymes and hepatocellular dysfunction have been reported. In very rare
cases, a fatal outcome has been reported.
Metformin
Clinical Trial Data and Post-marketing data
Table 3 presents adverse reactions by system organ class and by frequency category. Frequency
categories are based on information available from metformin Summary of Product Characteristics
available in the EU.
46
Immune system disorders
(see Skin and subcutaneous tissue disorders)
anaphylactic reaction
Table 3. The frequency of metformin adverse reactions identified from clinical trial and post-
marketing data
Adverse reaction
Frequency
Gastrointestinal disorders
gastrointestinal symptoms
6
Very common
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Very rare
vitamin B12 deficiency
7
Very rare
Nervous system disorders
metallic taste
Common
Hepatobiliary disorders
liver function disorders
Very rare
hepatitis
Very rare
Skin and subcutaneous disorders
urticaria Very rare
erythema Very rare
pruritis Very rare
6
Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite
occur most frequently during initiation of therapy and resolve spontaneously in most cases.
7
Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption
which may very rarely result in clinically significant vitamin B12 deficiency (e.g. megaloblastic
anaemia).
No data are available with regard to overdose of AVANDAMET.
Limited data are available with regard to overdose of rosiglitazone in humans. In clinical studies in
volunteers rosiglitazone has been administered at single oral doses of up to 20 mg and was well
tolerated.
A large overdose of metformin (or coexisting risks of lactic acidosis) may lead to lactic acidosis which
is a medical emergency and must be treated in hospital.
In the event of an overdose, it is recommended that appropriate supportive treatment is initiated as
dictated by the patient's clinical status. The most effective method to remove lactate and metformin is
haemodialysis, however rosiglitazone is highly protein bound and is not cleared by haemodialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Combinations of oral blood glucose lowering medicinal products, ATC
code: A10BD03
AVANDAMET combines two antihyperglycaemic agents with complimentary mechanisms of action
to improve glycaemic control in patients with type 2 diabetes: rosiglitazone maleate, a member of the
47
Metabolism and nutrition disorders
lactic acidosis
thiazolidinedione class and metformin hydrochloride, a member of the biguanide class.
Thiazolidinediones act primarily by reducing insulin resistance and biguanides act primarily by
decreasing endogenous hepatic glucose production.
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The antihyperglycaemic activity of rosiglitazone has been demonstrated in a number of animal models
of type 2 diabetes. In addition, rosiglitazone preserved ß-cell function as shown by increased
pancreatic islet mass and insulin content and prevented the development of overt hyperglycaemia in
animal models of type 2 diabetes. Rosiglitazone
did not stimulate pancreatic insulin secretion or
induce hypoglycaemia in rats and mice. The major metabolite (a para-hydroxy-sulphate) with high
affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in
obese mice. The clinical relevance of this observation has not been fully elucidated.
In clinical trials, the glucose lowering effects observed with rosiglitazone are gradual in onset with
near maximal reductions in fasting plasma glucose (FPG) evident following approximately 8 weeks of
therapy. The improved glycaemic control is associated with reductions in both fasting and post-
prandial glucose.
Rosiglitazone was associated with increases in weight. In mechanistic studies, the weight increase was
predominantly shown to be due to increased subcutaneous fat with decreased visceral and intra-hepatic
fat.
Consistent with the mechanism of action, rosiglitazone in combination with metformin reduced insulin
resistance and improved pancreatic ß-cell function. Improved glycaemic control was also associated
with significant decreases in free fatty acids. As a consequence of different but complementary
mechanisms of action, combination therapy of rosiglitazone
with
metformin resulted in additive
effects on glycaemic control in type 2 diabetic patients.
In studies with a maximal duration of three years, rosiglitazone given once or twice daily in dual oral
therapy with metformin produced a sustained improvement in glycaemic control (FPG and HbA1c). A
more pronounced glucose-lowering effect was observed in obese patients. An outcome study has not
been completed with rosiglitazone, therefore the long-term benefits associated with improved
glycaemic control of rosiglitazone have not been demonstrated.
An active controlled clinical trial (rosiglitazone up to 8 mg daily or metformin up to 2,000 mg daily)
of 24 weeks duration was performed in 197 children (10-17 years of age) with type 2 diabetes.
Improvement in HbA1c from baseline achieved statistical significance only in the metformin group.
Rosiglitazone failed to demonstrate non-inferiority to metformin. Following rosiglitazone treatment,
there were no new safety concerns noted in children compared to adult patients with type 2 diabetes
mellitus. No long-term efficacy and safety data are available in paediatric patients.
ADOPT (A Diabetes Outcome Progression Trial) was a multicentre, double-blind, controlled trial with
a treatment duration of 4-6 years (median duration of 4 years), in which rosiglitazone at doses of 4 to
8 mg/day was compared to metformin (500 mg to 2000 mg/day) and glibenclamide (2.5 to 15 mg/day)
in 4351 drug naive subjects recently diagnosed (≤3 years) with type 2 diabetes. Rosiglitazone
treatment significantly reduced the risk of reaching monotherapy failure (FPG>10.0 mmol/L) by 63%
relative to glibenclamide (HR 0.37, CI 0.30-0.45) and by 32% relative to metformin (HR 0.68,
CI 0.55-0.85) during the course of the study (up to 72 months of treatment). This translates to a
cumulative incidence of treatment failure of 10.3% for rosiglitazone, 14.8% for metformin and 23.3%
for glibenclamide treated patients. Overall, 43%, 47% and 42% of subjects in the rosiglitazone,
glibenclamide and metformin groups respectively withdrew due to reasons other than monotherapy
failure. The impact of these findings on disease progression or on microvascular or macrovascular
outcomes has not been determined (see section 4.8). In this study, the adverse events observed were
48
Rosiglitazone
Rosiglitazone is a selective agonist at the PPARγ (peroxisome proliferator activated receptor gamma)
nuclear receptor and is a member of the thiazolidinedione class of antihyperglycaemic agents. It
reduces glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver.
consistent with the known adverse event profile for each of the treatments, including continuing
weight gain with rosiglitazone. An additional observation of an increased incidence of bone fractures
was seen in women with rosiglitazone (see sections 4.4 and 4.8).
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Randomised Treatment
†
Mean (SD) dose at end of randomised treatment
Rosiglitazone (either SU or metformin) 6.7 (1.9) mg
Sulphonylurea (background metformin)
Glimepiride* 3.6 (1.8) mg
Metformin (background sulphonylurea) 1995.5 (682.6) mg
*Similar relative effective doses (i.e approximately half maximal dose) for other sulphonylureas
(glibenclamide and glicazide).
† Patients who took designated treatment as randomised in combination with the correct background
treatment and with evaluable data.
No difference in the number of adjudicated primary endpoint events for rosiglitazone (321/2220)
versus active control (323/2227) (HR 0.99, CI 0.85-1.16) was observed, meeting the pre-defined non-
inferiority criterion of 1.20 (non-inferiority p = 0.02). HR and CI for key secondary endpoints were:
all-cause death (HR 0.86, CI 0.68-1.08), MACE (Major Adverse Cardiac Events - cardiovascular
death, acute myocardial infarction, stroke) (HR 0.93, CI 0.74-1.15), cardiovascular death (HR 0.84, CI
0.59-1.18), acute myocardial infarction (HR 1.14, CI 0.80-1.63) and stroke (HR 0.72, CI 0.49-1.06). In
a sub-study at 18 months, add-on rosiglitazone dual therapy was non-inferior to the combination of
sulphonylurea plus metformin for lowering HbA1c. In the final analysis at 5 years, an adjusted mean
reduction from baseline in HbA1c of 0.14% for patients on rosiglitazone added to metformin versus an
increase of 0.17% for patients taking sulphonylurea added to metformin was seen during treatment
with randomised dual-combination therapy (p<0.0001 for treatment difference). An adjusted mean
reduction in HbA1c of 0.24% was seen for patients taking rosiglitazone added to sulphonylurea,
versus a reduction in HbA1c of 0.10% for patients taking metformin added to sulphonylurea,
(p=0.0083 for treatment difference). There was a significant increase in heart failure (fatal and non-
fatal) (HR 2.10, CI 1.35-3.27) and bone fractures (Risk Ratio 1.57, CI 1.26-1.97) in rosiglitazone-
containing treatments compared to active control (see sections 4.4 and 4.8). A total of 564 patients
withdrew from cardiovascular follow-up, which accounted for 12.3% of rosiglitazone patients and
13% of control patients; representing 7.2% of patient-years lost for cardiovascular events follow-up
and 2.0% of patient-years lost for all cause mortality follow-up.
Metformin
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial
plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via three mechanisms:
-
by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis
-
in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and
utilisation
-
by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin increases the transport capacity of specific types of membrane glucose transporters
(GLUT-1 and GLUT-4).
49
The RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in
Diabetes) trial was a large (4,447 subjects), open-label, prospective, controlled study (mean follow-up
5.5 years) in which patients with type 2 diabetes inadequately controlled with metformin or
sulphonylurea were randomised to add-on rosiglitazone or metformin or sulphonylurea. The mean
duration of diabetes in these patients was approximately 7 years. The adjudicated primary endpoint
was cardiovascular hospitalisation (which included hospitalisations for heart failure) or cardiovascular
death. Mean doses at the end of randomised treatment are shown in the following table:
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid
metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term
clinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels.
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a significant reduction of the absolute risk of any diabetes-related complication in the metformin
group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years),
p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups
(40.1 events/1,000 patient-years), p=0.0034
-
a significant reduction of the absolute risk of diabetes-related mortality: metformin
7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017
-
a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000
patient-years versus diet alone 20.6 events/1,000 patient-years (p=0.011), and versus the
combined sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years
(p=0.021)
-
a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000
patient-years, diet alone 18 events/1,000 patient-years (p=0.01).
5.2 Pharmacokinetic properties
AVANDAMET
Absorption
No statistically significant difference was observed between the absorption characteristics of
rosiglitazone and metformin from the AVANDAMET tablet and those obtained from rosiglitazone
maleate and metformin hydrochloride tablets, respectively.
Food had no effect on the AUC of rosiglitazone or metformin when AVANDAMET was administered
to healthy volunteers. In the fed state, C
max
was lower (22% rosiglitazone and 15% metformin) and
t
max
delayed (by approximately 1.5 h rosiglitazone and 0.5 h metformin). This food-effect is not
considered clinically significant.
The following statements reflect the pharmacokinetic properties of the individual active substances of
AVANDAMET.
Rosiglitazone
Absorption
Absolute bioavailability of rosiglitazone following both a 4 and an 8 mg oral dose is approximately
99%. Rosiglitazone plasma concentrations peak at around 1 h after dosing. Plasma concentrations are
approximately dose proportional over the therapeutic dose range.
Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), although a
small decrease in C
max
(approximately 20-28%) and a delay in t
max
(approximately 1.75 h) were
observed compared to dosing in the fasting state. These small changes are not clinically significant
and, therefore, it is not necessary to administer rosiglitazone at any particular time in relation to meals.
The absorption of rosiglitazone is not affected by increases in gastric pH.
Distribution
The volume of distribution of rosiglitazone is approximately 14 l in healthy volunteers. Plasma
protein binding of rosiglitazone is high (approximately 99.8%) and is not influenced by concentration
or age. The protein binding of the major metabolite (a para-hydroxy-sulphate) is very high
(> 99.99%).
Metabolism
Metabolism of rosiglitazone is extensive with no parent compound being excreted unchanged. The
major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with
sulphate and glucuronic acid. The contribution of the major metabolite (a para-hydroxy-sulphate) to
50
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood
glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with
metformin after failure of diet alone showed:
-
the overall antihyperglycaemic activity of rosiglitazone has not been fully elucidated in man and it
cannot be ruled out that the metabolite may contribute to the activity. However, this raises no safety
concern regarding target or special populations as hepatic impairment is contraindicated and the phase
III clinical studies included a considerable number of elderly patients and patients with mild to
moderate renal impairment.
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Since there is no significant
in vitro
inhibition of CYP1A2, 2A6, 2C19, 2D6, 2E1, 3A or 4A with
rosiglitazone, there is a low probability of significant metabolism-based interactions with substances
metabolised by these P450 enzymes. Rosiglitazone showed moderate inhibition of CYP2C8
(IC
50
18 µM) and low inhibition of CYP2C9 (IC
50
50 µM)
in vitro
(see section 4.5). An
in vivo
interaction study with warfarin indicated that rosiglitazone does not interact with CYP2C9 substrates
in vivo
.
Elimination
Total plasma clearance of rosiglitazone is around 3 l/h and the terminal elimination half-life of
rosiglitazone is approximately 3-4 h. There is no evidence for unexpected accumulation of
rosiglitazone after once or twice daily dosing. The major route of excretion is the urine with
approximately two-thirds of the dose being eliminated by this route, whereas faecal elimination
accounts for approximately 25% of dose. No intact active substance is excreted in urine or faeces.
The terminal half-life for radioactivity was about 130 h indicating that elimination of metabolites is
very slow. Accumulation of the metabolites in plasma is expected upon repeated dosing, especially
that of the major metabolite (a para-hydroxy-sulphate) for which an 8-fold accumulation is anticipated.
Special populations
Gender: In the pooled population pharmacokinetic analysis, there were no marked differences in the
pharmacokinetics of rosiglitazone between males and females.
Elderly: In the pooled population pharmacokinetic analysis
,
age was not found to influence the
pharmacokinetics of rosiglitazone to any significant extent
.
Children and adolescents: Population pharmacokinetic analysis including 96 paediatric patients aged
10 to 18 years and weighing 35 to 178 kg suggested similar mean CL/F in children and adults.
Individual CL/F in the paediatric population was in the same range as individual adult data. CL/F
seemed to be independent of age, but increased with weight in the paediatric population.
Hepatic impairment: In cirrhotic patients with moderate (Child-Pugh B) hepatic impairment, unbound
C
max
and AUC were 2- and 3-fold higher than in normal subjects. The inter-subject variability was
large, with a 7-fold difference in unbound AUC between patients.
Renal insufficiency: There are no clinically significant differences in the pharmacokinetics of
rosiglitazone in patients with renal impairment or end stage renal disease on chronic dialysis.
Metformin
Absorption
After an oral dose of metformin, t
max
is reached in 2.5 h. Absolute bioavailability of a 500 mg
metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed
fraction recovered in faeces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the
pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing
schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than
1 µg/ml. In controlled clinical trials, maximum metformin plasma levels (C
max
) did not exceed
4 µg/ml, even at maximum doses.
51
In vitro
studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor
contribution by CYP2C9.
Food decreases the extent and slightly delays the absorption of metformin. Following administration
of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min
prolongation of time to peak plasma concentration was observed. The clinical relevance of this
decrease is unknown.
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Metabolism
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination
Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular
filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is
approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to
that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of
metformin in plasma.
5.3 Preclinical safety data
No animal studies have been conducted with the combined products in AVANDAMET. The
following data are findings in studies performed with rosiglitazone or metformin individually.
Rosiglitazone
Undesirable effects observed in animal studies with possible relevance to clinical use were as follows:
An increase in plasma volume accompanied by decrease in red cell parameters and increase in heart
weight. Increases in liver weight, plasma ALT (dog only) and fat tissue were also observed. Similar
effects have been seen with other thiazolidinediones.
In reproductive toxicity studies, administration of rosiglitazone to rats during mid-late gestation was
associated with foetal death and retarded foetal development. In addition, rosiglitazone inhibited
ovarian oestradiol and progesterone synthesis and lowered plasma levels of these hormones resulting
in effects on oestrus/menstrual cycles and fertility (see section 4.4).
In an animal model for familial adenomatous polyposis (FAP), treatment with rosiglitazone at 200
times the pharmacologically active dose increased tumour multiplicity in the colon. The relevance of
this finding is unknown. However, rosiglitazone promoted differentiation and reversal of mutagenic
changes in human colon cancer cells
in vitro
. In addition, rosiglitazone was not genotoxic in a battery
of
in vivo
and
in vitro
genotoxicity studies and there was no evidence of colon tumours in lifetime
studies of rosiglitazone in two rodent species.
Metformin
Non-clinical data for metformin reveal no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to
reproduction.
6.
6.1 List of excipients
Tablet core
:
Sodium starch glycollate
Hypromellose (E464)
Microcrystalline cellulose (E460)
52
Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower
than the plasma peak and appears at approximately the same time. The red blood cells most likely
represent a secondary compartment of distribution. The mean V
d
ranged between 63 – 276 l.
Lactose monohydrate
Povidone (E1201)
Magnesium stearate.
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6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Opaque blisters (PVC/PVdC/aluminium). Packs of 14, 28, 56, 112 (2x56), 168 (3x56) and 180 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product should be disposed of in accordance with local requirements.
7.
SmithKline Beecham Ltd
980 Great West Road
Brentford, Middlesex
TW8 9GS
United Kingdom
8.
EU/1/03/258/007-009
EU/1/03/258/013
EU/1/03/258/017
EU/1/03/258/021
9.
Date of first authorisation: 20 October 2003
Date of latest renewal: 20 October 2008
53
Film coat:
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol
Iron oxide yellow (E172).
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.ema.europa.eu
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54
1.
Further information
1.
WHAT AVANDAMET IS AND WHAT IT IS USED FOR
Avandamet tablets are a combination of two different medicines
called
rosiglitazone
and
metformin.
These two medicines are used to treat
type 2 diabetes.
People with type 2 diabetes either don’t make enough insulin (a hormone that controls blood sugar
levels), or don’t respond normally to the insulin their body makes. Rosiglitazone and metformin work
together so your body makes better use of the insulin it produces, and this helps reduce your blood
sugar to a normal level. Avandamet can be used alone or with a sulphonylurea, another medicine for
diabetes.
2.
BEFORE YOU TAKE AVANDAMET
To help manage your diabetes, it is important that you follow any diet and lifestyle advice from your
doctor as well as taking Avandamet.
Don’t take Avandamet:
•
if you are allergic
(
hypersensitive
) to rosiglitazone or metformin or any of the other
ingredients of Avandamet (
listed in Section 6)
•
if you have had a heart attack or severe angina,
that’s being treated in hospital
•
if you have heart failure,
or have had heart failure in the past
•
if you have severe breathing difficulties
•
if you have liver disease
•
if you are a heavy drinker of alcohol
– if you regularly drink a lot,
or if you have
occasional sessions of heavy drinking (binge drinking)
•
if you have had diabetic ketoacidosis
(a complication of diabetes causing rapid weight
loss, nausea or vomiting)
•
if you have kidney disease
106
Read all of this leaflet carefully before you start taking this medicine.
-
-
If you have any further questions, ask your doctor or pharmacist.
•
if you are very dehydrated or have a severe infection
(see ‘While you take
Avandamet your doctor needs to know’ later in Section 2
)
•
if you are going to have an X-ray using an injected dye
(see ‘While you take
Avandamet your doctor needs to know’ later in Section 2
)
•
if you are breast-feeding
(see ‘Pregnancy and breast-feeding’ later in Section 2
).
Î
Check with your doctor
if you think any of these apply to you.
Don’t take Avandamet.
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Avandamet is not recommended for people aged under 18
, as the safety and effectiveness are not
known.
If you have been diagnosed with angina
(chest pain), or peripheral arterial disease (reduced blood
flow to the legs):
Î
Check with your doctor,
as
Avandamet may not be suitable for you.
Conditions to look out for
Avandamet and other medicines for diabetes can make some existing conditions worse, or cause
serious side effects. You must look out for certain symptoms while you are taking Avandamet, to
reduce the risk of any problems. See ‘
Conditions you need to look out for’
in Section 4.
Ovulation may restart
Women who are infertile due to a condition affecting their ovaries (such as
Polycystic Ovarian
Syndrome
), may start ovulating again when they start taking Avandamet. If this applies to you, use
appropriate contraception to avoid the possibility of an unplanned pregnancy
(see ‘Pregnancy and
breast-feeding’ later in Section 2).
Your kidney function will be checked
Your kidneys should be checked at least once a year – more often if you are over 65, or if your kidney
function is close to abnormal.
While you take Avandamet your doctor needs to know:
y
if you become dehydrated –
for example, after severe vomiting, diarrhoea or fever. These can
lead to severe loss of water (
dehydration
). Speak to your doctor, as you may need to stop taking
Avandamet for a short while
.
•
if you are going to have an operation under general anaesthetic.
Your doctor will advise you
to stop taking Avandamet for at least 48 hours before and after the operation.
•
if you are going to have an X-ray using an injected dye.
Your doctor will advise you to stop
taking Avandamet before the X-ray and for 48 hours after it. The doctor will check your kidney
function before restarting treatment.
107
Take special care with Avandamet
Taking other medicines
Tell your doctor or pharmacist if you are taking any other medicines, if you’ve taken any recently, or
if you start taking new ones. This includes herbal medicines and other medicines you bought without a
prescription.
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Pregnancy and breast-feeding
•
Avandamet is not recommended during pregnancy.
If you are pregnant or could be pregnant,
tell your doctor before you take Avandamet.
•
Don’t breast-feed
while you are taking Avandamet. The ingredients may pass into breast milk
and so may harm your baby.
Driving and using machines
This medicine should not affect your ability to drive or use machines.
Avandamet contains lactose
Avandamet tablets contain a small amount of lactose. Patients who are intolerant to lactose or have a
rare hereditary problem of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose
malabsorption
should not take this medicine.
3.
HOW TO TAKE AVANDAMET
Always take Avandamet tablets exactly as your doctor has told you. Do not take more than the
recommended dose. Check with your doctor or pharmacist if you are not sure.
How much to take
The usual starting dose
is one combined tablet (2 mg rosiglitazone and 1000 mg metformin), taken
twice a day, morning and evening. (You can also take this dose as two 1 mg/500 mg tablets, twice a
day.)
After about 8 weeks your doctor may need to increase your dose. The maximum dose is 4 mg
rosiglitazone and 1000 mg metformin, taken twice a day. (You can also take this dose as two
2 mg/500 mg tablets, twice a day.)
How to take
Swallow the tablets with some water.
It is best to take Avandamet with food,
or just after food. This helps to reduce any problems with
your stomach (including indigestion, nausea, vomiting and diarrhoea).
Take your tablets around the same time every day and follow any dietary advice that your doctor has
given you.
If you take more Avandamet than you should
108
Certain medicines are especially likely to affect the amount of sugar in your blood:
•
steroids (used to treat
inflammation
) such as prednisolone or dexamethasone
•
beta-2-agonists (used to treat
asthma
), such as salbutamol or salmeterol
•
diuretics (used to
get rid of water
), such as furosemide or indapamide
•
ACE inhibitors (used to treat
high blood pressure
), such as enalapril or captopril
•
gemfibrozil (used to
lower cholesterol
)
•
rifampicin (used to treat
tuberculosis
and other infections)
•
cimetidine (used to reduce
stomach acid
).
Î
Tell a doctor or pharmacist if you are taking any of these.
Your blood sugar will be checked,
and your dose of Avandamet may need to be changed.
If you accidentally take too many tablets, contact your doctor or pharmacist for advice.
If you forget to take Avandamet
Don’t take extra tablets to make up for a missed dose. Just take your next dose at the usual time.
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4.
POSSIBLE SIDE EFFECTS
Like all medicines, Avandamet can cause side effects, but not everybody gets them.
Conditions you need to look out for
Allergic reactions:
These are very rare in people taking Avandamet. Signs include:
•
raised and itchy rash (
hives
)
•
swelling, sometimes of the face or mouth (
angioedema
), causing difficulty in breathing
•
collapse.
Î
Contact a doctor immediately
if you get any of these symptoms.
Stop taking
Avandamet.
Lactic acidosis:
An increase in the amount of lactic acid in the blood
(lactic acidosis)
is a very rare
side effect of metformin. This most often affects people who have severe kidney disease. Symptoms of
lactic acidosis include:
•
rapid breathing
•
feeling cold
•
stomach pain, nausea and vomiting.
Î
Contact a doctor immediately
if you get these symptoms.
Stop taking
Avandamet.
Fluid retention and heart failure:
Avandamet can cause you to retain water (
fluid retention
) which
leads to swelling and weight gain. Extra body fluid can make some existing heart problems worse or
lead to heart failure. This is more likely if you are also taking other medicines for your diabetes (like
insulin), if you have kidney problems, or if you are over 65.
Check your weight regularly; if it goes
up rapidly, tell your doctor.
Symptoms of heart failure include:
•
shortness of breath, waking up short of breath at night
•
getting tired easily after light physical activity such as walking
•
rapid increase in your weight
•
swollen ankles or feet.
Î
Tell your doctor as soon as possible
if you get any of these symptoms - either for the first time
or if they get worse.
Low blood sugar
(
hypoglycaemia
): If you are taking Avandamet with other medicines for diabetes, it
is more likely that your blood sugar could fall below the normal level. Early symptoms of low blood
sugar are:
y
shaking, sweating, faintness
y
nervousness, palpitations
y
hunger.
The severity can increase, leading to confusion and loss of consciousness.
Î
Tell your doctor as soon as possible
if you get any of these symptoms. The dose of your
medicines may need to be reduced.
Liver problems:
Before you start taking Avandamet you will have a blood sample taken to check
your liver function. This check may be repeated at intervals. These may be signs of liver problems:
•
nausea and vomiting
•
stomach (
abdominal
) pain
109
Don’t stop taking Avandamet
Take Avandamet for as long as your doctor recommends. If you stop taking Avandamet, your blood
sugar will not be controlled, and you may become unwell. Talk to your doctor if you want to stop.
•
loss of appetite
•
dark-coloured urine.
Î
Tell your doctor as soon as possible
if you get these symptoms.
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Broken bones:
Bone fractures can occur in people with diabetes. The chances of this happening may
be higher in people, particularly women, taking rosiglitazone for more than one year. The most
common are breaks in feet, hands and arms.
Very common side effects
These may affect
more than
1 in 10
people:
•
stomach pain, feeling sick (
nausea
), vomiting, diarrhoea or loss of appetite.
Common side effects
These may affect
up to 1 in 10
people:
•
chest pain (
angina
)
•
broken bones
•
reduction in blood count (
anaemia
)
•
small increases in blood cholesterol, increased amount of fats in the blood
•
increased weight, increased appetite
•
dizziness
•
constipation
•
lower blood sugar than normal (
hypoglycaemia
)
•
swelling (
oedema)
due to water retention
•
metallic taste in the mouth.
Rare side effects
These may affect
up to 1 in 1,000
people:
•
fluid in the lungs (
pulmonary oedema
) causing breathlessness
•
heart failure
•
swelling of the retina at the back of the eye (
macular oedema
)
•
liver doesn’t function as well as it should (
increase in liver enzymes
).
Very rare side effects
These may affect
up to 1 in 10,000
people:
•
allergic reactions
•
inflammation of the liver (
hepatitis
)
•
decrease in amount of vitamin B
12
in the blood
•
rapid and excessive weight gain caused by fluid retention
•
increase of lactic acid in the blood
.
If you get side effects
Î
Tell your doctor or pharmacist
if any of the side effects listed gets severe or troublesome, or if
you notice any side effects not listed in this leaflet.
5.
HOW TO STORE AVANDAMET
Keep out of the reach and sight of children.
Do not use Avandamet after the expiry date shown on the pack.
110
Eye problems:
Swelling of the retina at the back of the eye which can cause blurred vision (
macular
oedema
) can be a problem for people with diabetes. New or worse cases of macular oedema have
occurred on rare occasions in people taking Avandamet and similar medicines.
Î
Discuss with your doctor
any concerns about your eyesight.
This medicine does not require any special storage conditions.
If you have any unwanted tablets, don’t put them in waste water or household rubbish. Ask your
pharmacist how to dispose of tablets you don’t need. This will help to protect the environment.
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FURTHER INFORMATION
What Avandamet contains
The active substances are rosiglitazone and metformin. Avandamet tablets come in different strengths.
Each tablet contains either: 1 mg rosiglitazone and 500 mg metformin; 2 mg rosiglitazone and 500 mg
metformin; 2 mg rosiglitazone and 1000 mg metformin or 4 mg rosiglitazone and 1000 mg metformin.
The other ingredients are: sodium starch glycollate, hypromellose (E464), microcrystalline cellulose
(E460), lactose monohydrate, povidone (E1201), magnesium stearate, titanium dioxide (E171),
macrogol, iron oxide yellow or red (E172).
What Avandamet looks like and contents of the pack
Avandamet
1 mg/500 mg
tablets are yellow and marked "gsk" on one side and "1/500" on the other.
Avandamet 2 mg/500 mg
tablets are pale pink, marked "gsk" on one side and "2/500" on the other.
These strengths are supplied in blister packs containing 28, 56, 112, 3x112 or 360 film-coated tablets.
Avandamet 2 mg/1000 mg
tablets are yellow, marked "gsk" on one side and "2/1000" on the other.
Avandamet 4 mg/1000 mg
tablets are pink, marked "gsk" on one side and "4/1000" on the other.
These strengths are supplied in blister packs containing 14, 28, 56, 2x56, 3x56 or 180 film-coated
tablets.
Not all pack sizes or tablet strengths may be available in your country.
Marketing Authorisation Holder
: SmithKline Beecham Ltd, 980 Great West Road, Brentford,
Middlesex, TW8 9GS, United Kingdom.
Manufacturer
: Glaxo Wellcome S.A., Avenida de Extremadura 3, 09400 Aranda de Duero, Burgos,
Spain.
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
111
6.
België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 (0)2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 21 11
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Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
dk-info@gsk.com
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 6938100
nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel.: + 49 (0)89 36044 8701
produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
Eesti
GlaxoSmithKline Eesti OÜ
Tel: + 372 6676 900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
at.info@gsk.com
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (0)22 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
Portugal
GlaxoSmithKline – Produtos Farmacêuticos, Lda.
Tel: + 351 21 412 95 00
FI.PT@gsk.com
France
Laboratoire GlaxoSmithKline
Tél.: + 33 (0)1 39 17 84 44
diam@gsk.com
România
GlaxoSmithKline (GSK) S.R.L.
Tel: + 4021 3028 208
Ireland
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0)1 280 25 00
medical.x.si@gsk.com
Ísland
GlaxoSmithKline ehf.
Sími: + 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
112
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Italia
GlaxoSmithKline S.p.A.
Tel: + 39 (0)45 9218 111
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30
Finland.tuoteinfo@gsk.com
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Sverige
GlaxoSmithKline AB
Tel: + 46 (0)8 638 93 00
info.produkt@gsk.com
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
GlaxoSmithKline UK
Tel: + 44 (0)800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site:
http://www.ema.europa.eu
113
Κύπρος
GlaxoSmithKline Cyprus Ltd
Τηλ: + 357 22 39 70 00
Source: European Medicines Agency
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