Avandamet

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1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 1 mg/500 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 1 mg of rosiglitazone (as rosiglitazone maleate) and 500 mg of metformin 
hydrochloride (corresponding to metformin free base 390 mg). 
 
Excipients: 
Each tablet contains lactose (approximately 6 mg). 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Yellow film-coated tablets marked "gsk" on one side and "1/500" on the other. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 

 
4.2 Posology and method of administration 
 
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) 



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- 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. 

 
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). 
 
4.3 Contraindications 
 
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. 

 
4.4 Special warnings and precautions for use 
 
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, 



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prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with 
hypoxia. 
 
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). 
 
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. 



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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). 
 
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. 
 
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 



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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. 
 
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). 
 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 Cmax 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). 
 



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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. 
 
Concomitant administration of rosiglitazone with the oral antihyperglycaemic agents glibenclamide 
and acarbose did not result in any clinically relevant pharmacokinetic interactions. 
 
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. 
 
4.6 Pregnancy and lactation 
 
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). 
 
4.7 Effects on ability to drive and use machines 
 
AVANDAMET has no or negligible influence on the ability to drive and use machines. 
 
 
4.8 Undesirable effects 
 
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. 



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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). 
 
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.  
 



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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 

 
Blood and the lymphatic system disorders 
anaemia Common Common Common 
granulocytopaenia   Common 
 
Metabolism and nutrition disorders 
hypercholesterolaemia1 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 failure2  Common Common 
cardiac ischaemia3* Common Common Common 
 
Gastrointestinal disorders 
constipation Common Common Common 
 
Musculoskeletal and connective tissue disorders 
bone fractures4 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. 



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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). 
 
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.  
 



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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 
 
Immune system disorders (see Skin and subcutaneous tissue disorders) 
anaphylactic reaction Very rare 
 
Eye disorders 
macular oedema Rare 
 
Cardiac disorders 
congestive heart failure/pulmonary oedema Rare 
 
Hepatobiliary disorders 
hepatic dysfunction, primarily evidenced by elevated hepatic enzymes5 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.  
 



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Table 3. The frequency of metformin adverse reactions identified from clinical trial and post-
marketing data  
 
Adverse reaction Frequency 
 
Gastrointestinal disorders 
gastrointestinal symptoms6 Very common 
 
Metabolism and nutrition disorders 
lactic acidosis Very rare 
vitamin B12 deficiency7 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). 
 
4.9 Overdose 
 
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. PHARMACOLOGICAL PROPERTIES 
 
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 



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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.  
 
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. 
 
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 



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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). 
 
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: 
 
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). 
 



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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. 
 
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: 
- 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, Cmax was lower (22% rosiglitazone and 15% metformin) and 
tmax 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 Cmax (approximately 20-28%) and a delay in tmax (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 



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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. 
 
In vitro studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor 
contribution by CYP2C9. 
 
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 
(IC50 18 µM) and low inhibition of CYP2C9 (IC50 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 
Cmax 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, tmax 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 (Cmax) did not exceed 
4 µg/ml, even at maximum doses. 



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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. 
 
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 Vd ranged between 63 – 276 l. 
 
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. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Sodium starch glycollate  
Hypromellose (E464) 
Microcrystalline cellulose (E460) 



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Lactose monohydrate 
Povidone (E1201) 
Magnesium stearate. 
 
Film coat: 
Hypromellose (E464) 
Titanium dioxide (E171) 
Macrogol  
Iron oxide yellow (E172). 
 
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. MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex 
TW8 9GS 
United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/03/258/001-003 
EU/1/03/258/015 
EU/1/03/258/019 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 October 2003 
Date of latest renewal: 20 October 2008 
 
10. DATE OF REVISION OF THE TEXT 
 
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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1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 2 mg/500 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 2 mg of rosiglitazone (as rosiglitazone maleate) and 500 mg of metformin 
hydrochloride (corresponding to metformin free base 390 mg). 
 
Excipients: 
Each tablet contains lactose (approximately 11 mg) 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Pale pink film-coated tablets marked "gsk" on one side and "2/500" on the other. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 

 
4.2 Posology and method of administration 
 
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) 



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- 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. 

 
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). 
 
4.3 Contraindications 
 
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. 

 
4.4 Special warnings and precautions for use 
 
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, 



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prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with 
hypoxia. 
 
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). 
 
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. 



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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). 
 
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. 
 
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 



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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. 
 
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). 
 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 Cmax 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). 
 



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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. 
 
Concomitant administration of rosiglitazone with the oral antihyperglycaemic agents glibenclamide 
and acarbose did not result in any clinically relevant pharmacokinetic interactions. 
 
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. 
 
4.6 Pregnancy and lactation 
 
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). 
 
4.7 Effects on ability to drive and use machines 
 
AVANDAMET has no or negligible influence on the ability to drive and use machines. 
 
 
4.8 Undesirable effects 
 
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. 



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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). 
 
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.  
 



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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 

 
Blood and the lymphatic system disorders 
Anaemia Common Common Common 
granulocytopaenia   Common 
 
Metabolism and nutrition disorders 
hypercholesterolaemia1 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 failure2  Common Common 
cardiac ischaemia3* Common Common Common 
 
Gastrointestinal disorders 
Constipation Common Common Common 
 
Musculoskeletal and connective tissue disorders 
bone fractures4 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. 



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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). 
 
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.  
 



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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 
 
Immune system disorders (see Skin and subcutaneous tissue disorders) 
anaphylactic reaction Very rare 
 
Eye disorders 
macular oedema Rare 
 
Cardiac disorders 
congestive heart failure/pulmonary oedema Rare 
 
Hepatobiliary disorders 
hepatic dysfunction, primarily evidenced by elevated hepatic enzymes5 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.  
 



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Table 3. The frequency of metformin adverse reactions identified from clinical trial and post-
marketing data  
 
Adverse reaction Frequency 
 
Gastrointestinal disorders 
gastrointestinal symptoms6 Very common 
 
Metabolism and nutrition disorders 
lactic acidosis Very rare 
vitamin B12 deficiency7 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). 
 
4.9 Overdose 
 
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. PHARMACOLOGICAL PROPERTIES 
 
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.  



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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. 
 
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 
consistent with the known adverse event profile for each of the treatments, including continuing 



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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). 
 
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: 
 
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). 
 



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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. 
 
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: 
- 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, Cmax was lower (22% rosiglitazone and 15% metformin) and 
tmax 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 Cmax (approximately 20-28%) and a delay in tmax (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 



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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. 
 
In vitro studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor 
contribution by CYP2C9. 
 
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 
(IC50 18 µM) and low inhibition of CYP2C9 (IC50 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 
Cmax 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, tmax 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 (Cmax) did not exceed 
4 µg/ml, even at maximum doses. 



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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. 
 
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 Vd ranged between 63 – 276 l. 
 
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. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Sodium starch glycollate  
Hypromellose (E464) 
Microcrystalline cellulose (E460) 



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Lactose monohydrate 
Povidone (E1201) 
Magnesium stearate. 
 
 
Film coat: 
Hypromellose (E464) 
Titanium dioxide (E171) 
Macrogol  
Iron oxide red (E172). 
 
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. MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex 
TW8 9GS 
United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/03/258/004-006 
EU/1/03/258/016 
EU/1/03/258/020 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 October 2003 
Date of latest renewal: 20 October 2008 
 
10. DATE OF REVISION OF THE TEXT 
 



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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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1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 2 mg/1000 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 2 mg of rosiglitazone (as rosiglitazone maleate) and 1000 mg of metformin 
hydrochloride (corresponding to metformin free base 780 mg). 
 
Excipients: 
Each tablet contains lactose (approximately 11 mg) 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Yellow film-coated tablets marked "gsk" on one side and "2/1000" on the other. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 

 
4.2 Posology and method of administration 
 
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. 
 



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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. 

 
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). 
 
4.3 Contraindications 
 
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. 
 
4.4 Special warnings and precautions for use 
 
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, 



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prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with 
hypoxia. 
 
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). 
 
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. 



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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). 
 
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. 
 
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 



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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. 
 
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). 
 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 Cmax 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). 
 



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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. 
 
Concomitant administration of rosiglitazone with the oral antihyperglycaemic agents glibenclamide 
and acarbose did not result in any clinically relevant pharmacokinetic interactions. 
 
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. 
 
4.6 Pregnancy and lactation 
 
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). 
 
4.7 Effects on ability to drive and use machines 
 
AVANDAMET has no or negligible influence on the ability to drive and use machines. 
 
 
 
4.8 Undesirable effects 
 
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. 



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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). 
 
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.  
 



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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 

 
Blood and the lymphatic system disorders 
anaemia Common Common Common 
granulocytopaenia   Common 
 
Metabolism and nutrition disorders 
hypercholesterolaemia1 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 failure2  Common Common 
cardiac ischaemia3* Common Common Common 
 
Gastrointestinal disorders 
constipation Common Common Common 
 
Musculoskeletal and connective tissue disorders 
bone fractures4 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%.   
 



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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). 
 
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.  
 



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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 
 
Immune system disorders (see Skin and subcutaneous tissue disorders) 
anaphylactic reaction Very rare 
 
Eye disorders 
macular oedema Rare 
 
Cardiac disorders 
congestive heart failure/pulmonary oedema Rare 
 
Hepatobiliary disorders 
hepatic dysfunction, primarily evidenced by elevated hepatic enzymes5 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.  
 



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Table 3. The frequency of metformin adverse reactions identified from clinical trial and post-
marketing data  
 
Adverse reaction Frequency 
 
Gastrointestinal disorders 
gastrointestinal symptoms6 Very common 
 
Metabolism and nutrition disorders 
lactic acidosis Very rare 
vitamin B12 deficiency7 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). 
 
4.9 Overdose 
 
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. PHARMACOLOGICAL PROPERTIES 
 
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 



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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.  
 
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. 
 
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 



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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). 
 
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: 
 
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). 
 



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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. 
 
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: 
- 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, Cmax was lower (22% rosiglitazone and 15% metformin) and 
tmax 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 Cmax (approximately 20-28%) and a delay in tmax (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 



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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. 
 
In vitro studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor 
contribution by CYP2C9. 
 
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 
(IC50 18 µM) and low inhibition of CYP2C9 (IC50 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 
Cmax 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, tmax 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 (Cmax) did not exceed 
4 µg/ml, even at maximum doses. 
 



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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. 
 
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 Vd ranged between 63 – 276 l. 
 
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. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Sodium starch glycollate  
Hypromellose (E464) 
Microcrystalline cellulose (E460) 



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Lactose monohydrate 
Povidone (E1201) 
Magnesium stearate. 
 
Film coat: 
Hypromellose (E464) 
Titanium dioxide (E171) 
Macrogol  
Iron oxide yellow (E172). 
 
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. MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex 
TW8 9GS 
United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
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/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 October 2003 
Date of latest renewal: 20 October 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 



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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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1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 4 mg/1000 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 4 mg of rosiglitazone (as rosiglitazone maleate) and 1000 mg of metformin 
hydrochloride (corresponding to metformin free base 780 mg). 
 
Excipients: 
Each tablet contains lactose (approximately 23 mg) 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Pink film-coated tablets marked "gsk" on one side and "4/1000" on the other. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 

 
4.2 Posology and method of administration 
 
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. 
 



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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. 

 
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). 
 
4.3 Contraindications 
 
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. 
 
4.4 Special warnings and precautions for use 
 
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, 



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prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with 
hypoxia. 
 
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). 
 
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. 



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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). 
 
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. 
 
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 



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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. 
 
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). 
 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 Cmax 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). 
 
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, 



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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. 
 
Concomitant administration of rosiglitazone with the oral antihyperglycaemic agents glibenclamide 
and acarbose did not result in any clinically relevant pharmacokinetic interactions. 
 
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. 
 
4.6 Pregnancy and lactation 
 
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). 
 
4.7 Effects on ability to drive and use machines 
 
AVANDAMET has no or negligible influence on the ability to drive and use machines. 
 
 
 
 
4.8 Undesirable effects 
 
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. 



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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). 
 
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.  
 



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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 

 
Blood and the lymphatic system disorders 
anaemia Common Common Common 
granulocytopaenia   Common 
 
Metabolism and nutrition disorders 
hypercholesterolaemia1 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 failure2  Common Common 
cardiac ischaemia3* Common Common Common 
 
Gastrointestinal disorders 
constipation Common Common Common 
 
Musculoskeletal and connective tissue disorders 
bone fractures4 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. 



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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). 
 
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.  
 



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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 
 
Immune system disorders (see Skin and subcutaneous tissue disorders) 
anaphylactic reaction Very rare 
 
Eye disorders 
macular oedema Rare 
 
Cardiac disorders 
congestive heart failure/pulmonary oedema Rare 
 
Hepatobiliary disorders 
hepatic dysfunction, primarily evidenced by elevated hepatic enzymes5 Rare 
 
Skin and subcutaneous tissue disorders (see Immune system disorders) 
angioedema Very rare 
skin reaction (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.  
 



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Table 3. The frequency of metformin adverse reactions identified from clinical trial and post-
marketing data  
 
Adverse reaction Frequency 
 
Gastrointestinal disorders 
gastrointestinal symptoms6 Very common 
 
Metabolism and nutrition disorders 
lactic acidosis Very rare 
vitamin B12 deficiency7 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). 
 
4.9 Overdose 
 
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. PHARMACOLOGICAL PROPERTIES 
 
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 



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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.  
 
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. 
 
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 



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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). 
 
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: 
 
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). 
 



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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. 
 
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: 
- 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, Cmax was lower (22% rosiglitazone and 15% metformin) and 
tmax 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 Cmax (approximately 20-28%) and a delay in tmax (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 



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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. 
 
In vitro studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor 
contribution by CYP2C9. 
 
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 
(IC50 18 µM) and low inhibition of CYP2C9 (IC50 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 
Cmax 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, tmax 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 (Cmax) did not exceed 
4 µg/ml, even at maximum doses. 



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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. 
 
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 Vd ranged between 63 – 276 l. 
 
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. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Sodium starch glycollate  
Hypromellose (E464) 
Microcrystalline cellulose (E460) 



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Lactose monohydrate 
Povidone (E1201) 
Magnesium stearate. 
 
Film coat: 
Hypromellose (E464) 
Titanium dioxide (E171) 
Macrogol  
Iron oxide red (E172). 
 
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. MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex 
TW8 9GS 
United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/03/258/010-012 
EU/1/03/258/014 
EU/1/03/258/018 
EU/1/03/258/022 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 October 2003 
Date of latest renewal: 20 October 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 



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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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ANNEX II 
 
A. MANUFACTURING AUTHORISATION HOLDER(S) 

RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OF THE MARKETING AUTHORISATION 
 



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A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
Name and address of the manufacturer(s) responsible for batch release 
 
Glaxo Wellcome, S.A. 
Avenida de Extremadura, 3 
09400 Aranda de Duero 
Burgos 
Spain 
 
 
B. CONDITIONS OF THE MARKETING AUTHORISATION 
 
• CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON 

THE MARKETING AUTHORISATION HOLDER 
 
Medicinal product subject to medical prescription.  
 
• CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Not applicable. 
 
• OTHER CONDITIONS 
 
Pharmacovigilance system 
 
The Marketing Authorisation Holder (MAH) must ensure that the system of pharmacovigilance, as 
described in version 7.2 presented in Module 1.8.1. of the Marketing Authorisation, is in place and 
functioning before and whilst the product is on the market. 
 
Risk Management Plan 
 
The Marketing Authorisation Holder commits to performing the studies and additional 
pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in version 4 of the Risk 
Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and 
any subsequent updates of the RMP agreed by the CHMP. 
 
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the 
updated RMP should be submitted at the same time as the next Periodic Safety Update Report 
(PSUR). 
 
In addition, an updated RMP should be submitted: 
− When new information is received that may impact on the current Safety Specification, 

Pharmacovigilance Plan or risk minimisation activities. 
− Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being 

reached. 
1. At the request of the EMEA. 
 
PSURs 
 
Following the renewal of the Marketing Authorisation, the Marketing Authorisation Holder will 
submit yearly PSURs until otherwise decided by the CHMP. 
 



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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



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A. LABELLING 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON (WITH BLUE BOX)  
(EXCLUDING MULTIPACKS) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 1 mg/500 mg film-coated tablets 
rosiglitazone/metformin HCl 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 1 mg of rosiglitazone (as maleate) and 500 mg of metformin hydrochloride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 tablets 
56 tablets 
112 tablets 
360 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Use only as directed by your doctor. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 



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OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/258/001 28 tablets 
EU/1/03/258/002 56 tablets 
EU/1/03/258/003 112 tablets 
EU/1/03/258/019 360 tablets 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandamet 1 mg/500 mg 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER LABEL (WITH BLUE BOX) 
MULTIPACKS ONLY (3x112 TABLETS) 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 1 mg/500 mg film-coated tablets 
rosiglitazone/metformin HCl 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 1 mg of rosiglitazone (as maleate) and 500 mg of metformin hydrochloride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack comprising 3 packs, each containing 112 film-coated tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Use only as directed by your doctor. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS
 



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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/258/015 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandamet 1 mg/500 mg 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
INTERMEDIATE CARTON (WITHOUT BLUE BOX)  
 MULTIPACKS ONLY (112 TABLETS) 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 1 mg/500 mg film-coated tablets 
rosiglitazone/metformin HCl 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 1 mg of rosiglitazone (as maleate) and 500 mg of metformin hydrochloride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
112 tablets. 
Component of a multipack comprising 3 packs, each containing 112 film-coated tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Use only as directed by your doctor. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS
 



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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/258/015 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandamet 1 mg/500 mg 



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 1 mg/500 mg tablets 
rosiglitazone/metformin HCl 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON (WITH BLUE BOX)  
(EXCLUDING MULTIPACKS) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 2 mg/500 mg film-coated tablets 
rosiglitazone/metformin HCl 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 2 mg of rosiglitazone (as maleate) and 500 mg of metformin hydrochloride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 tablets 
56 tablets 
112 tablets 
360 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Use only as directed by your doctor. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 



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OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/258/004 28 tablets 
EU/1/03/258/005 56 tablets 
EU/1/03/258/006 112 tablets 
EU/1/03/258/020 360 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandamet 2 mg/500 mg 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER LABEL (WITH BLUE BOX) 
MULTIPACKS ONLY (3x112 TABLETS) 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 2 mg/500 mg film-coated tablets 
rosiglitazone/metformin HCl 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 2 mg of rosiglitazone (as maleate) and 500 mg of metformin hydrochloride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack comprising 3 packs, each containing 112 film-coated tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Use only as directed by your doctor. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS
 



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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/258/016 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandamet 2 mg/500 mg 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
INTERMEDIATE CARTON (WITHOUT BLUE BOX) 
MULTIPACKS ONLY (3x112 TABLETS) 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 2 mg/500 mg film-coated tablets 
rosiglitazone/metformin HCl 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 2 mg of rosiglitazone (as maleate) and 500 mg of metformin hydrochloride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
112 tablets. 
Component of a multipack comprising 3 packs, each containing 112 film-coated tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Use only as directed by your doctor. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS
 



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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/258/016 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandamet 2 mg/500 mg 



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 2 mg/500 mg tablets 
rosiglitazone/metformin HCl 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON (WITH BLUE BOX)  
(EXCLUDING MULTIPACKS)  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 2 mg/1000 mg film-coated tablets 
rosiglitazone/metformin HCl 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 2 mg of rosiglitazone (as maleate) and 1000 mg of metformin hydrochloride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
56 tablets 
180 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Use only as directed by your doctor. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 



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OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/258/007 14 tablets 
EU/1/03/258/008 28 tablets 
EU/1/03/258/009 56 tablets 
EU/1/03/258/021 180 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandamet 2 mg/1000 mg 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER LABEL (WITH BLUE BOX) 
MULTIPACKS ONLY (2x56 TABLETS, WRAPPED IN CLEAR PLASTIC) 
MULTIPACKS ONLY (3x56 TABLETS, PACKED IN BOX) 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 2 mg/1000 mg film-coated tablets 
rosiglitazone/metformin HCl 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 2 mg of rosiglitazone (as maleate) and 1000 mg of metformin hydrochloride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack comprising 2 packs, each containing 56 film-coated tablets. 
Multipack comprising 3 packs, each containing 56 film-coated tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Use only as directed by your doctor. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 



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OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/258/013, 56 tablets, component of a 112 tablet multipack. 
EU/1/03/258/017, 56 tablets, component of a 168 tablet multipack. 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandamet 2 mg/1000 mg 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
INTERMEDIATE CARTON (WITHOUT BLUE BOX)  
MULTIPACKS ONLY (56 TABLETS) 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 2 mg/1000 mg film-coated tablets 
rosiglitazone/metformin HCl 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 2 mg of rosiglitazone (as maleate) and 1000 mg of metformin hydrochloride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 tablets. 
Component of a multipack comprising 2 packs, each containing 56 film-coated tablets. 
 
56 tablets. 
Component of a multipack comprising 3 packs, each containing 56 film-coated tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Use only as directed by your doctor. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



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9. SPECIAL STORAGE CONDITIONS
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/258/013, 56 tablets, component of a 112 tablet multipack. 
EU/1/03/258/017, 56 tablets, component of a 168 tablet multipack. 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandamet 2 mg/1000 mg 



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 2 mg/1000 mg tablets 
rosiglitazone/metformin HCl 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON (WITH BLUE BOX)  
(EXCLUDING MULTIPACKS)  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 4 mg/1000 mg film-coated tablets 
rosiglitazone/metformin HCl 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 4 mg of rosiglitazone (as maleate) and 1000 mg of metformin hydrochloride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
56 tablets 
180 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Use only as directed by your doctor. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 



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OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/258/010 14 tablets 
EU/1/03/258/011 28 tablets 
EU/1/03/258/012 56 tablets 
EU/1/03/258/022 180 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandamet 4 mg/1000 mg 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER LABEL (WITH BLUE BOX) 
MULTIPACKS ONLY (2x56 TABLETS, WRAPPED IN CLEAR PLASTIC) 
MULTIPACKS ONLY (3x56 TABLETS, PACKED IN BOX) 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 4 mg/1000 mg film-coated tablets 
rosiglitazone/metformin HCl 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 4 mg of rosiglitazone (as maleate) and 1000 mg of metformin hydrochloride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack comprising 2 packs, each containing 56 film-coated tablets. 
Multipack comprising 3 packs, each containing 56 film-coated tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Use only as directed by your doctor. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 



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OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/258/014, 56 tablets, component of a 112 tablet multipack. 
EU/1/03/258/018, 56 tablets, component of a 168 tablet multipack. 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandamet 4 mg/1000 mg 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
INTERMEDIATE CARTON (WITHOUT BLUE BOX)  
MULTIPACKS ONLY (56 TABLETS) 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 4 mg/1000 mg film-coated tablets 
rosiglitazone/metformin HCl 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 4 mg of rosiglitazone (as maleate) and 1000 mg of metformin hydrochloride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 tablets. 
Component of a multipack comprising 2 packs, each containing 56 film-coated tablets. 
 
56 tablets. 
Component of a multipack comprising 3 packs, each containing 56 film-coated tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Use only as directed by your doctor. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



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9. SPECIAL STORAGE CONDITIONS
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/258/014, 56 tablets, component of a 112 tablet multipack. 
EU/1/03/258/018, 56 tablets, component of a 168 tablet multipack. 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandamet 4 mg/1000 mg 



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDAMET 4 mg/1000 mg tablets 
rosiglitazone/metformin HCl 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



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B. PACKAGE LEAFLET 



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PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

AVANDAMET 1 mg/500 mg film-coated tablets 
AVANDAMET 2 mg/500 mg film-coated tablets 

AVANDAMET 2 mg/1000 mg film-coated tablets 
AVANDAMET 4 mg/1000 mg film-coated tablets 

rosiglitazone/metformin HCl 
 
Read all of this leaflet carefully before you start taking this medicine. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours.  
- If any of the side effects gets serious, or if you notice any side effects not listed in this 

leaflet, tell your doctor or pharmacist. 
 
In this leaflet:  
1. What Avandamet is and what it is used for 
2. Before you take Avandamet 
3. How to take Avandamet 
4. Possible side effects 
5 How to store Avandamet 
6. 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  



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• 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). 
     Check with your doctor if you think any of these apply to you. Don’t take Avandamet. 

 
Take special care with Avandamet 
 
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): 

     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:  

 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. 

 



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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.   
 
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). 

 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. 

 
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  



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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.  
 
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. 
 
 
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. 

 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. 

 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. 

 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: 
 shaking, sweating, faintness 
 nervousness, palpitations  
 hunger.  

The severity can increase, leading to confusion and loss of consciousness.  
 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 



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• loss of appetite 
• dark-coloured urine.  

 Tell your doctor as soon as possible if you get these symptoms. 
 
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.   

 Discuss with your doctor any concerns about your eyesight.   
 
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 B12 in the blood 
• rapid and excessive weight gain caused by fluid retention  
• increase of lactic acid in the blood. 

If you get side effects 
 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. 



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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. 
 
 
6. 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. 
 



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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 
 

България 
ГлаксоСмитКлайн ЕООД 
Teл.: + 359 2 953 10 34 
 

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 
 



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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 
 

Κύπρος 
GlaxoSmithKline Cyprus Ltd 
Τηλ: + 357 22 39 70 00 

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 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET