Avandia
1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDIA 2 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains rosiglitazone maleate corresponding to 2 mg rosiglitazone. 
 
Excipient 
Contains lactose (approximately 108 mg). 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Pink film-coated tablets debossed with “GSK” on one side and "2" on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rosiglitazone is indicated in the treatment of type 2 diabetes mellitus:  
 
as monotherapy 
– in patients (particularly overweight patients) inadequately controlled by diet and exercise for 

whom metformin is inappropriate because of contraindications or intolerance 
 
as dual oral therapy in combination with 
– metformin, in patients (particularly overweight patients) with insufficient glycaemic control 

despite maximal tolerated dose of monotherapy with metformin 
– a sulphonylurea, only in patients who show intolerance to metformin or for whom metformin is 

contraindicated, with insufficient glycaemic control despite monotherapy with a sulphonylurea 
 
as triple oral therapy in combination with 
– metformin and a sulphonylurea, in patients (particularly overweight patients) with insufficient 

glycaemic control despite dual oral therapy (see section 4.4). 
 
4.2 Posology and method of administration 
 
Rosiglitazone therapy is usually initiated at 4 mg/day. This dose can be increased to 8 mg/day after 
eight weeks if greater glycaemic control is required. In patients administered rosiglitazone in 
combination with a sulphonylurea, an increase in rosiglitazone 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 4.4 and 4.8). 
 
Rosiglitazone may be given once or twice a day. 
 
Rosiglitazone may be taken with or without food. 
 
Elderly (see section 4.4 Fluid retention and cardiac failure) 
No dose adjustment is required in the elderly. 
 

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Patients with renal impairment (see section 4.4 Fluid retention and cardiac failure) 
No dose adjustment is required in patients with mild and moderate renal insufficiency. Limited data 
are available in patients with severe renal insufficiency (creatinine clearance < 30 ml/min) and 
therefore rosiglitazone should be used with caution in these patients. 
 
Patients with hepatic impairment 
Rosiglitazone should not be used in patients with hepatic impairment. 
 
Children and adolescents 
There are no data available on the use of rosiglitazone in patients under 10 years of age. For children 
aged 10 to 17 years, there are limited data on rosiglitazone as monotherapy (see sections 5.1 and 5.2). 
The available data do not support efficacy in the paediatric population and therefore such use is not 
recommended. 
 
4.3 Contraindications 
 
Use of rosiglitazone is contraindicated in patients with: 
 
− known hypersensitivity to rosiglitazone or to any of the excipients  
 
− cardiac failure or history of cardiac failure (NYHA class I to IV) 
 
− an Acute Coronary Syndrome (unstable angina, NSTEMI and STEMI) (see section 4.4) 
 
− hepatic impairment 
 
-  diabetic ketoacidosis or diabetic pre-coma.  
 
4.4 Special warnings and precautions for use 
 
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 or 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. Increased monitoring of the patient is 
recommended if rosiglitazone is used in combination with metformin and insulin.  Rosiglitazone 
should be discontinued if any deterioration in cardiac status occurs.  
 
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 and rosiglitazone are 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, 

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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. 
 
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 (see 
section 4.8). There is limited experience with rosiglitazone in patients with elevated liver enzymes 
(ALT >2.5X upper limit of normal). Therefore, liver enzymes should be checked prior to the initiation 
of therapy with rosiglitazone in all patients and periodically thereafter based on clinical judgement. 
Therapy with rosiglitazone should not be initiated in patients with increased baseline liver enzyme 
levels (ALT >2.5X upper limit of normal) or with any other evidence of liver disease. If ALT levels 
are increased to >3X upper limit of normal during rosiglitazone therapy, liver enzyme levels should be 
reassessed as soon as possible. If ALT levels remain >3X 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 rosiglitazone should 
be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, drug 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 rosiglitazone. 
 
Hypoglycaemia 
Patients receiving rosiglitazone in combination therapy with a sulphonylurea or with 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. 
 
Triple oral therapy 
The use of rosiglitazone in triple oral therapy, in combination with metformin and a sulphonylurea, 
may be associated with increased risks for fluid retention and heart failure, as well as hypoglycaemia 
(see section 4.8). Increased monitoring of the patient is recommended and adjustment of the dose of 
sulphonylurea may be necessary. The decision to initiate triple oral therapy should include 
consideration of the alternative to switch the patient to insulin. 
 
 

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Bone disorders 
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. 
 
Others 
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 and if a patient wishes to become 
pregnant or if pregnancy occurs the treatment should be discontinued (see section 4.6). 
 
Rosiglitazone should be used with caution in patients with severe renal insufficiency (creatinine 
clearance < 30 ml/min). 
 
Rosiglitazone should be used with caution during concomitant administration of CYP2C8 inhibitors 
(e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely. 
Rosiglitazone dose adjustment within the recommended posology or changes in diabetic treatment 
should be considered (see section 4.5). 
 
AVANDIA 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 
 
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, 
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 with the oral anti-diabetic agents metformin, glibenclamide and acarbose 
did not result in any clinically relevant pharmacokinetic interactions with rosiglitazone. Moderate 
ingestion of alcohol with rosiglitazone has no effect on glycaemic control. 
 
No clinically relevant interactions with digoxin, the CYP2C9 substrate warfarin, the CYP3A4 
substrates nifedipine, ethinylestradiol or norethindrone were observed after co-administration with 
rosiglitazone. 
 
4.6 Pregnancy and lactation 
 
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 

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shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Rosiglitazone 
should not be used during pregnancy. 
 
Rosiglitazone has been detected in the milk of experimental animals. It is not known whether breast-
feeding will lead to exposure of the infant to drug. Rosiglitazone should therefore not be used in 
women who are breast-feeding. 
 
4.7 Effects on ability to drive and use machines 
 
AVANDIA has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
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. 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, 
< 1/10; and uncommon ≥ 1/1000, < 1/100. 
 
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.  
 
Table 1. The frequency of adverse reactions identified from clinical trial data 
 
Adverse reaction Frequency of adverse reaction by treatment regimen 
 RSG RSG + 

MET 
RSG + SU RSG +MET +SU 

 
Blood and the lymphatic system disorders 
anaemia Common Common Common Common 
leucopaenia   Common  
thrombocytopaenia   Common  
granulocytopaenia    Common 
 
Metabolism and nutrition disorders 
hypercholesterolaemia1 Common Common Common Common 
hypertriglyceridaemia Common  Common  
hyperlipaemia Common Common Common Common 
weight increase Common Common Common Common 
increased appetite Common  Uncommon  
hypoglycaemia  Common Very common Very common 
 
Nervous system disorders 
dizziness*  Common Common  
headache*    Common 
 
Cardiac disorders 

cardiac failure2  Common Common Common 
cardiac ischaemia3* Common Common Common Common 

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Gastrointestinal disorders 
constipation Common Common Common Common 
 
Musculoskeletal and connective tissue disorders 
bone fractures4 Common Common Common  
myalgia*    Common 
 
General disorders and administration site conditions 
oedema Common Common Very common Very common 
RSG - Rosiglitazone monotherapy; RSG + MET - Rosiglitazone with metformin; RSG + SU - 
Rosiglitazone with sulphonylurea; RSG + MET + SU - Rosiglitazone with metformin and 
sulphonylurea 
 
*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 
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%. Moreover in patients 
with congestive heart failure NYHA class I-II, a placebo-controlled one-year trial demonstrated 
worsening or possible worsening of heart failure 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 

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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. Frequencies are defined as: rare 
≥1/10,000, <1/1000 and very rare <1/10,000 including isolated reports. 
 
Table 2. The frequency of adverse reactions identified from post-marketing data 
 

5 Rare cases of elevated liver enzymes and hepatocellular dysfunction have been reported. In very rare 
cases a fatal outcome has been reported. 
 
4.9 Overdose 
 
Limited data are available with regard to overdose in humans. In clinical studies in volunteers 
rosiglitazone has been administered at single oral doses of up to 20 mg and was well tolerated. 
 
In the event of an overdose, it is recommended that appropriate supportive treatment should be 
initiated, as dictated by the patient's clinical status. Rosiglitazone is highly protein bound and is not 
cleared by haemodialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: oral blood glucose lowering drugs, thiazolidinediones, ATC code: A10 

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, pruritus, rash) Very rare 

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BG 02 
 
Rosiglitazone is a selective agonist at the PPARγ (peroxisomal proliferator activated receptor gamma) 
nuclear receptor and is a member of the thiazolidinedione class of anti-diabetic agents. It reduces 
glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver. 
 
Preclinical data 
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 (para-hydroxy-sulphate) with high 
affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in 
obese mouse. The clinical relevance of this observation has not been fully elucidated. 
 
Clinical trials data 
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 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, dual oral 
therapy of rosiglitazone with a sulphonylurea or 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 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 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 
weight gain with rosiglitazone. An additional observation of an increased incidence of bone fractures 

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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. 
 
5.2 Pharmacokinetic properties 
 
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 hour 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% to 28%) and a delay in tmax (ca.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 litres 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 (para-hydroxy-sulphate) is very high (>99.99%). 

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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 (para-hydroxy-sulphate) to the 
overall anti-diabetic 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 to 4 hours. 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 drug is excreted in urine or faeces. The terminal 
half-life for radioactivity was about 130 hours 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 (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. 
 
5.3 Preclinical safety data 
 
Adverse 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. 
 

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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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Sodium starch glycollate (Type A)  
hypromellose  
microcrystalline cellulose  
lactose monohydrate 
magnesium stearate. 
 
Film coating (Opadry pink OY-L-24802): 
Hypromellose 6cP 
Titanium dioxide E171  
Macrogol 3000  
Lactose monohydrate  
Glycerol triacetate  
Iron oxide red E172. 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 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 blister packs (PVC/ aluminium). 56, 112, 168 or 180 film-coated tablets or 56 film-coated 
tablets, unit dose pack. 
 
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 

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SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom. 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/137/002-004, EU/1/00/137/013, EU/1/00/137/016 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 11 July 2000 
Date of latest renewal: 11 July 2005 
 
 
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 
 
AVANDIA 4 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains rosiglitazone maleate corresponding to 4 mg rosiglitazone. 
 
Excipient 
Contains lactose (approximately 105 mg). 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Orange film-coated tablets debossed with “GSK” on one side and "4" on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rosiglitazone is indicated in the treatment of type 2 diabetes mellitus:  
 
as monotherapy 
– in patients (particularly overweight patients) inadequately controlled by diet and exercise for 

whom metformin is inappropriate because of contraindications or intolerance 
 
as dual oral therapy in combination with 
– metformin, in patients (particularly overweight patients) with insufficient glycaemic control 

despite maximal tolerated dose of monotherapy with metformin 
– a sulphonylurea, only in patients who show intolerance to metformin or for whom metformin is 

contraindicated, with insufficient glycaemic control despite monotherapy with a sulphonylurea 
 
as triple oral therapy in combination with 
– metformin and a sulphonylurea, in patients (particularly overweight patients) with insufficient 

glycaemic control despite dual oral therapy (see section 4.4). 
 
4.2 Posology and method of administration 
 
Rosiglitazone therapy is usually initiated at 4 mg/day. This dose can be increased to 8 mg/day after 
eight weeks if greater glycaemic control is required. In patients administered rosiglitazone in 
combination with a sulphonylurea, an increase in rosiglitazone 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 4.4 and 4.8). 
 
Rosiglitazone may be given once or twice a day. 
 
Rosiglitazone may be taken with or without food. 
 
Elderly (see section 4.4 Fluid retention and cardiac failure) 
No dose adjustment is required in the elderly. 
 

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Patients with renal impairment (see section 4.4 Fluid retention and cardiac failure) 
No dose adjustment is required in patients with mild and moderate renal insufficiency. Limited data 
are available in patients with severe renal insufficiency (creatinine clearance < 30 ml/min) and 
therefore rosiglitazone should be used with caution in these patients. 
 
Patients with hepatic impairment 
Rosiglitazone should not be used in patients with hepatic impairment. 
 
Children and adolescents 
There are no data available on the use of rosiglitazone in patients under 10 years of age. For children 
aged 10 to 17 years, there are limited data on rosiglitazone as monotherapy (see sections 5.1 and 5.2). 
The available data do not support efficacy in the paediatric population and therefore such use is not 
recommended. 
 
4.3 Contraindications 
 
Use of rosiglitazone is contraindicated in patients with: 
 
− known hypersensitivity to rosiglitazone or to any of the excipients  
 
− cardiac failure or history of cardiac failure (NYHA class I to IV) 
 
− an Acute Coronary Syndrome (unstable angina, NSTEMI and STEMI) (see section 4.4) 
 
− hepatic impairment 
 
-  diabetic ketoacidosis or diabetic pre-coma. 
 
4.4 Special warnings and precautions for use 
 
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 or 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. Increased monitoring of the patient is 
recommended if rosiglitazone is used in combination with metformin and insulin. Rosiglitazone 
should be discontinued if any deterioration in cardiac status occurs.  
 
 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 and rosiglitazone are 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, 

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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. 
 
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 (see 
section 4.8). There is limited experience with rosiglitazone in patients with elevated liver enzymes 
(ALT >2.5X upper limit of normal). Therefore, liver enzymes should be checked prior to the initiation 
of therapy with rosiglitazone in all patients and periodically thereafter based on clinical judgement. 
Therapy with rosiglitazone should not be initiated in patients with increased baseline liver enzyme 
levels (ALT >2.5X upper limit of normal) or with any other evidence of liver disease. If ALT levels 
are increased to >3X upper limit of normal during rosiglitazone therapy, liver enzyme levels should be 
reassessed as soon as possible. If ALT levels remain >3X 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 rosiglitazone should 
be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, drug 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 rosiglitazone. 
 
Hypoglycaemia 
Patients receiving rosiglitazone in combination therapy with a sulphonylurea or with 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. 
 
Triple oral therapy 
The use of rosiglitazone in triple oral therapy, in combination with metformin and a sulphonylurea, 
may be associated with increased risks for fluid retention and heart failure, as well as hypoglycaemia 
(see section 4.8). Increased monitoring of the patient is recommended and adjustment of the dose of 
sulphonylurea may be necessary. The decision to initiate triple oral therapy should include 
consideration of the alternative to switch the patient to insulin. 
 
 

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Bone disorders 
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. 
 
Others 
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 and if a patient wishes to become 
pregnant or if pregnancy occurs the treatment should be discontinued (see section 4.6). 
 
Rosiglitazone should be used with caution in patients with severe renal insufficiency (creatinine 
clearance < 30 ml/min). 
 
Rosiglitazone should be used with caution during concomitant administration of CYP2C8 inhibitors 
(e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely. 
Rosiglitazone dose adjustment within the recommended posology or changes in diabetic treatment 
should be considered (see section 4.5). 
 
AVANDIA 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 
 
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, 
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 with the oral anti-diabetic agents metformin, glibenclamide and acarbose 
did not result in any clinically relevant pharmacokinetic interactions with rosiglitazone. Moderate 
ingestion of alcohol with rosiglitazone has no effect on glycaemic control. 
 
No clinically relevant interactions with digoxin, the CYP2C9 substrate warfarin, the CYP3A4 
substrates nifedipine, ethinylestradiol or norethindrone were observed after co-administration with 
rosiglitazone. 
 
4.6 Pregnancy and lactation 
 
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 

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shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Rosiglitazone 
should not be used during pregnancy. 
 
Rosiglitazone has been detected in the milk of experimental animals. It is not known whether breast-
feeding will lead to exposure of the infant to drug. Rosiglitazone should therefore not be used in 
women who are breast-feeding. 
 
4.7 Effects on ability to drive and use machines 
 
AVANDIA has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
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. 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, 
< 1/10; and uncommon ≥ 1/1000, < 1/100. 
 
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.  
 
Table 1. The frequency of adverse reactions identified from clinical trial data 
 
Adverse reaction Frequency of adverse reaction by treatment regimen 
 RSG RSG + 

MET 
RSG + SU RSG +MET +SU 

 
Blood and the lymphatic system disorders 
anaemia Common Common Common Common 
leucopaenia   Common  
thrombocytopaenia   Common  
granulocytopaenia    Common 
 
Metabolism and nutrition disorders 
hypercholesterolaemia1 Common Common Common Common 
hypertriglyceridaemia Common  Common  
hyperlipaemia Common Common Common Common 
weight increase Common Common Common Common 
increased appetite Common  Uncommon  
hypoglycaemia  Common Very common Very common 
 
Nervous system disorders 
dizziness*  Common Common  
headache*    Common 
 
Cardiac disorders 

cardiac failure2  Common Common Common 
cardiac ischaemia3* Common Common Common Common 

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Gastrointestinal disorders 
constipation Common Common Common Common 
 
Musculoskeletal and connective tissue disorders 
bone fractures4 Common Common Common  
myalgia*    Common 
 
General disorders and administration site conditions 
oedema Common Common Very common Very common 
RSG - Rosiglitazone monotherapy; RSG + MET - Rosiglitazone with metformin; RSG + SU - 
Rosiglitazone with sulphonylurea; RSG + MET + SU - Rosiglitazone with metformin and 
sulphonylurea 
 
*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 
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%. Moreover in patients 
with congestive heart failure NYHA class I-II, a placebo-controlled one-year trial demonstrated 
worsening or possible worsening of heart failure 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 

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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. Frequencies are defined as: rare 
≥1/10,000, <1/1000 and very rare <1/10,000 including isolated reports. 
 
Table 2. The frequency of adverse reactions identified from post-marketing data 
 
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, pruritus, 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. 
 
4.9 Overdose 
 
Limited data are available with regard to overdose in humans. In clinical studies in volunteers 
rosiglitazone has been administered at single oral doses of up to 20 mg and was well tolerated. 
 
In the event of an overdose, it is recommended that appropriate supportive treatment should be 
initiated, as dictated by the patient's clinical status. Rosiglitazone is highly protein bound and is not 
cleared by haemodialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 

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Pharmacotherapeutic group: oral blood glucose lowering drugs, thiazolidinediones, ATC code: A10 
BG 02 
 
Rosiglitazone is a selective agonist at the PPARγ (peroxisomal proliferator activated receptor gamma) 
nuclear receptor and is a member of the thiazolidinedione class of anti-diabetic agents. It reduces 
glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver. 
 
Preclinical data 
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 (para-hydroxy-sulphate) with high 
affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in 
obese mouse. The clinical relevance of this observation has not been fully elucidated. 
 
Clinical trials data 
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 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, dual oral 
therapy of rosiglitazone with a sulphonylurea or 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 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 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. 
 
5.2 Pharmacokinetic properties 
 
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 hour 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% to 28%) and a delay in tmax (ca.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 litres in healthy volunteers. Plasma 
protein binding of rosiglitazone is high (approximately 99.8%) and is not influenced by concentration 

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or age. The protein binding of the major metabolite (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 (para-hydroxy-sulphate) to the 
overall anti-diabetic 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 to 4 hours. 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 drug is excreted in urine or faeces. The terminal 
half-life for radioactivity was about 130 hours 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 (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. 
 
5.3 Preclinical safety data 
 
Adverse 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. 

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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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Sodium starch glycollate (Type A)  
hypromellose  
microcrystalline cellulose  
lactose monohydrate 
magnesium stearate. 
 
Film coating (Opadry orange OY-L-23028): 
Hypromellose 6cP 
Titanium dioxide E171  
Macrogol 3000  
Purified talc 
Lactose monohydrate  
Glycerol triacetate  
Iron oxide red E172 
Iron oxide yellow E172. 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 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 blister packs (PVC/ aluminium). 7, 28, 56, 84, 90 or 112 film-coated tablets or 56 film-coated 
tablets, unit dose pack. 
 
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. 

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25 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom. 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/137/005-009, EU/1/00/137/014, EU/1/00/137/017 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 11 July 2000 
Date of latest renewal: 11 July 2005 
 
 
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 
 
AVANDIA 8 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains rosiglitazone maleate corresponding to 8 mg rosiglitazone. 
 
Excipient 
Contains lactose (approximately 209 mg). 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Red-brown film-coated tablets debossed with “GSK” on one side and "8" on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rosiglitazone is indicated in the treatment of type 2 diabetes mellitus:  
 
as monotherapy 
– in patients (particularly overweight patients) inadequately controlled by diet and exercise for 

whom metformin is inappropriate because of contraindications or intolerance 
 
as dual oral therapy in combination with 
– metformin, in patients (particularly overweight patients) with insufficient glycaemic control 

despite maximal tolerated dose of monotherapy with metformin 
– a sulphonylurea, only in patients who show intolerance to metformin or for whom metformin is 

contraindicated, with insufficient glycaemic control despite monotherapy with a sulphonylurea 
 
as triple oral therapy in combination with 
– metformin and a sulphonylurea, in patients (particularly overweight patients) with insufficient 

glycaemic control despite dual oral therapy (see section 4.4). 
 
4.2 Posology and method of administration 
 
Rosiglitazone therapy is usually initiated at 4 mg/day. This dose can be increased to 8 mg/day after 
eight weeks if greater glycaemic control is required. In patients administered rosiglitazone in 
combination with a sulphonylurea, an increase in rosiglitazone 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 4.4 and 4.8). 
 
Rosiglitazone may be given once or twice a day. 
 
Rosiglitazone may be taken with or without food. 
 
Elderly (see section 4.4 Fluid retention and cardiac failure) 
No dose adjustment is required in the elderly. 
 

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Patients with renal impairment (see section 4.4 Fluid retention and cardiac failure) 
No dose adjustment is required in patients with mild and moderate renal insufficiency. Limited data 
are available in patients with severe renal insufficiency (creatinine clearance < 30 ml/min) and 
therefore rosiglitazone should be used with caution in these patients. 
 
Patients with hepatic impairment 
Rosiglitazone should not be used in patients with hepatic impairment. 
 
Children and adolescents 
There are no data available on the use of rosiglitazone in patients under 10 years of age. For children 
aged 10 to 17 years, there are limited data on rosiglitazone as monotherapy (see sections 5.1 and 5.2). 
The available data do not support efficacy in the paediatric population and therefore such use is not 
recommended. 
 
4.3 Contraindications 
 
Use of rosiglitazone is contraindicated in patients with: 
 
− known hypersensitivity to rosiglitazone or to any of the excipients  
 
− cardiac failure or history of cardiac failure (NYHA class I to IV) 
 
− an Acute Coronary Syndrome (unstable angina, NSTEMI and STEMI) (see section 4.4) 
 
− hepatic impairment 
 
-  diabetic ketoacidosis or diabetic pre-coma. 
 
4.4 Special warnings and precautions for use 
 
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 or 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. Increased monitoring of the patient is 
recommended if rosiglitazone is used in combination with metformin and insulin.  Rosiglitazone 
should be discontinued if any deterioration in cardiac status occurs.  
 
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 and rosiglitazone are 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, 

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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. 
 
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 (see 
section 4.8). There is limited experience with rosiglitazone in patients with elevated liver enzymes 
(ALT >2.5X upper limit of normal). Therefore, liver enzymes should be checked prior to the initiation 
of therapy with rosiglitazone in all patients and periodically thereafter based on clinical judgement. 
Therapy with rosiglitazone should not be initiated in patients with increased baseline liver enzyme 
levels (ALT >2.5X upper limit of normal) or with any other evidence of liver disease. If ALT levels 
are increased to >3X upper limit of normal during rosiglitazone therapy, liver enzyme levels should be 
reassessed as soon as possible. If ALT levels remain >3X 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 rosiglitazone should 
be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, drug 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 rosiglitazone. 
 
Hypoglycaemia 
Patients receiving rosiglitazone in combination therapy with a sulphonylurea or with 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. 
 
Triple oral therapy 
The use of rosiglitazone in triple oral therapy, in combination with metformin and a sulphonylurea, 
may be associated with increased risks for fluid retention and heart failure, as well as hypoglycaemia 
(see section 4.8). Increased monitoring of the patient is recommended and adjustment of the dose of 
sulphonylurea may be necessary. The decision to initiate triple oral therapy should include 
consideration of the alternative to switch the patient to insulin. 
 
 

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Bone disorders 
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. 
 
Others 
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 and if a patient wishes to become 
pregnant or if pregnancy occurs the treatment should be discontinued (see section 4.6). 
 
Rosiglitazone should be used with caution in patients with severe renal insufficiency (creatinine 
clearance < 30 ml/min). 
 
Rosiglitazone should be used with caution during concomitant administration of CYP2C8 inhibitors 
(e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely. 
Rosiglitazone dose adjustment within the recommended posology or changes in diabetic treatment 
should be considered (see section 4.5). 
 
AVANDIA 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 
 
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, 
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 with the oral anti-diabetic agents metformin, glibenclamide and acarbose 
did not result in any clinically relevant pharmacokinetic interactions with rosiglitazone. Moderate 
ingestion of alcohol with rosiglitazone has no effect on glycaemic control. 
 
No clinically relevant interactions with digoxin, the CYP2C9 substrate warfarin, the CYP3A4 
substrates nifedipine, ethinylestradiol or norethindrone were observed after co-administration with 
rosiglitazone. 
 
4.6 Pregnancy and lactation 
 
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 

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shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Rosiglitazone 
should not be used during pregnancy. 
 
Rosiglitazone has been detected in the milk of experimental animals. It is not known whether breast-
feeding will lead to exposure of the infant to drug. Rosiglitazone should therefore not be used in 
women who are breast-feeding. 
 
4.7 Effects on ability to drive and use machines 
 
AVANDIA has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
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. 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, 
< 1/10; and uncommon ≥ 1/1000, < 1/100. 
 
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.  
 
Table 1. The frequency of adverse reactions identified from clinical trial data 
 
Adverse reaction Frequency of adverse reaction by treatment regimen 
 RSG RSG + 

MET 
RSG + SU RSG +MET +SU 

 
Blood and the lymphatic system disorders 
anaemia Common Common Common Common 
leucopaenia   Common  
thrombocytopaenia   Common  
granulocytopaenia    Common 
 
Metabolism and nutrition disorders 
hypercholesterolaemia1 Common Common Common Common 
hypertriglyceridaemia Common  Common  
hyperlipaemia Common Common Common Common 
weight increase Common Common Common Common 
increased appetite Common  Uncommon  
hypoglycaemia  Common Very common Very common 
 
Nervous system disorders 
dizziness*  Common Common  
headache*    Common 
 
Cardiac disorders 

cardiac failure2  Common Common Common 
cardiac ischaemia3* Common Common Common Common 

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Gastrointestinal disorders 
constipation Common Common Common Common 
 
Musculoskeletal and connective tissue disorders 
bone fractures4 Common Common Common  
myalgia*    Common 
 
General disorders and administration site conditions 
oedema Common Common Very common Very common 
RSG - Rosiglitazone monotherapy; RSG + MET - Rosiglitazone with metformin; RSG + SU - 
Rosiglitazone with sulphonylurea; RSG + MET + SU - Rosiglitazone with metformin and 
sulphonylurea 
 
*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 
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%. Moreover in patients 
with congestive heart failure NYHA class I-II, a placebo-controlled one-year trial demonstrated 
worsening or possible worsening of heart failure 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 

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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. Frequencies are defined as: rare 
≥1/10,000, <1/1000 and very rare <1/10,000 including isolated reports. 
 
Table 2. The frequency of adverse reactions identified from post-marketing data 
 

5 Rare cases of elevated liver enzymes and hepatocellular dysfunction have been reported. In very rare 
cases a fatal outcome has been reported. 
 
4.9 Overdose 
 
Limited data are available with regard to overdose in humans. In clinical studies in volunteers 
rosiglitazone has been administered at single oral doses of up to 20 mg and was well tolerated. 
 
In the event of an overdose, it is recommended that appropriate supportive treatment should be 
initiated, as dictated by the patient's clinical status. Rosiglitazone is highly protein bound and is not 
cleared by haemodialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: oral blood glucose lowering drugs, thiazolidinediones, ATC code: A10 

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, pruritus, rash) Very rare 

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BG 02 
 
Rosiglitazone is a selective agonist at the PPARγ (peroxisomal proliferator activated receptor gamma) 
nuclear receptor and is a member of the thiazolidinedione class of anti-diabetic agents. It reduces 
glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver. 
 
Preclinical data 
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 (para-hydroxy-sulphate) with high 
affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in 
obese mouse. The clinical relevance of this observation has not been fully elucidated. 
 
Clinical trials data 
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 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, dual oral 
therapy of rosiglitazone with a sulphonylurea or 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 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 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 
weight gain with rosiglitazone. An additional observation of an increased incidence of bone fractures 
was seen in women with rosiglitazone (see sections 4.4 and 4.8). 

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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. 
 
5.2 Pharmacokinetic properties 
 
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 hour 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% to 28%) and a delay in tmax (ca.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 litres 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 (para-hydroxy-sulphate) is very high (>99.99%). 
 

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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 (para-hydroxy-sulphate) to the 
overall anti-diabetic 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 to 4 hours. 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 drug is excreted in urine or faeces. The terminal 
half-life for radioactivity was about 130 hours 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 (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. 
 
5.3 Preclinical safety data 
 
Adverse 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 

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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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Sodium starch glycollate (Type A)  
hypromellose  
microcrystalline cellulose  
lactose monohydrate 
magnesium stearate. 
 
Film coating (Opadry pink OY-L-24803): 
Hypromellose 6cP 
Titanium dioxide E171  
Macrogol 3000  
Lactose monohydrate  
Glycerol triacetate  
Iron oxide red E172. 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 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 blister packs (PVC/ aluminium). 7, 28, 84, 90 or 112 film-coated 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. 

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8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/137/010-012, EU/1/00/137/015, EU/1/00/137/018 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 11 July 2000 
Date of latest renewal: 11 July 2005 
 
 
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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38 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 Production 
Z.I. Du Terras 
53100 Mayenne 
France 
 
or 
 
Glaxo Wellcome S.A. 
Avenida de Extremadura 3 
09400 Aranda de Duero 
Burgos 
Spain 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
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 MAH 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 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, any 
updated RMP should be submitted at the same time as the following 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 

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

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41 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDIA 2 mg film-coated tablets 
rosiglitazone 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains rosiglitazone maleate corresponding to 2 mg rosiglitazone 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 film-coated tablets  
112 film-coated tablets 
168 film-coated tablets  
180 film-coated tablets  
56 film-coated tablets, unit dose pack 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use 
Use only as directed by your doctor 
 
 
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/1/00/137/002  56  tablets 
EU/1/00/137/003  112 tablets  
EU/1/00/137/013  168 tablets 
EU/1/00/137/016  180 tablets 
EU/1/00/137/004  56 tablet unit dose pack 
 
 
13. BATCH NUMBER 
 
LOT 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandia 2 mg 

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

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46 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDIA 4 mg film-coated tablets 
rosiglitazone 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains rosiglitazone maleate corresponding to 4 mg rosiglitazone 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
7 film-coated tablets  
28 film-coated tablets  
56 film-coated tablets 
84 film-coated tablets  
90 film-coated tablets  
112 film-coated tablets  
56 film-coated tablets, unit dose pack 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use 
Use only as directed by your doctor 
 
 
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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47 

 
 
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/1/00/137/005  7 tablets 
EU/1/00/137/006  28 tablets 
EU/1/00/137/007  56 tablets 
EU/1/00/137/014  84 tablets 
EU/1/00/137/017  90 tablets 
EU/1/00/137/008  112 tablets 
EU/1/00/137/009  56 tablet unit dose pack 
 
 
13. BATCH NUMBER 
 
LOT 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandia 4 mg 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDIA 4 mg tablets 
rosiglitazone 
 
 
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 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDIA 8 mg film-coated tablets 
rosiglitazone 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains rosiglitazone maleate corresponding to 8 mg rosiglitazone 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
7 film-coated tablets 
28 film-coated tablets 
84 film-coated tablets 
90 film-coated tablets 
112 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use 
Use only as directed by your doctor 
 
 
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/1/00/137/010  7 tablets 
EU/1/00/137/011  28 tablets 
EU/1/00/137/015  84 tablets 
EU/1/00/137/018  90 tablets 
EU/1/00/137/012  112 tablets 
 
 
13. BATCH NUMBER 
 
LOT 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
avandia 8 mg 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVANDIA 8 mg tablets 
rosiglitazone 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
LOT 
 
 
5. OTHER 
 
 

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52 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 

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53 

PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

AVANDIA 2 mg film-coated tablets 
AVANDIA 4 mg film-coated tablets 
AVANDIA 8 mg film-coated tablets 

rosiglitazone 
 
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 Avandia is and what it is used for 
2. Before you take Avandia 
3. How to take Avandia 
4. Possible side effects 
5 How to store Avandia 
6. Further information 
 
 
1. WHAT AVANDIA IS AND WHAT IT IS USED FOR 
 
Avandia is 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.  Avandia helps to reduce your blood sugar towards a normal level, by helping your body 
make better use of the insulin it produces. 
 
Avandia can be used alone or in combination with other medicines to treat diabetes (such as 
metformin or a sulphonylurea). 
 
 
2. BEFORE YOU TAKE AVANDIA 
 
To help manage your diabetes, it is important that you follow any diet and lifestyle advice from your 
doctor as well as taking Avandia. 
 
Don’t take Avandia: 

• if you are allergic (hypersensitive) to rosiglitazone or any of the other ingredients of 
Avandia (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 liver disease 
• if you have had diabetic ketoacidosis (a complication of diabetes causing rapid weight 

loss, nausea or vomiting) 

     Check with your doctor if you think any of these apply to you. Don’t take Avandia. 
 
Take special care with Avandia 
 
Avandia is not recommended for people aged under 18, as the effectiveness in children has not 
been shown. 
 

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54 

If you have been diagnosed with angina (chest pain), or peripheral arterial disease (reduced blood 
flow to the legs): 

     Check with your doctor, as Avandia may not be suitable for you. 
 
Conditions to look out for 
Avandia 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 Avandia, 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 Avandia. 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).  
 
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:  
• gemfibrozil (used to lower cholesterol) 
• rifampicin (used to treat tuberculosis and other infections) 

 Tell a doctor or pharmacist if you are taking any of these. Your blood sugar will be checked, 
and your dose of Avandia may need to be changed. 

 
Pregnancy and breast-feeding 
• Avandia is not recommended during pregnancy. If you are pregnant or could be pregnant, tell 

your doctor. 
 
• Don’t breast-feed while you are taking Avandia. 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. 
 
Avandia contains lactose  
Avandia 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 AVANDIA 
 
Always take Avandia 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 4 mg a day.  This can be taken as one 4 mg tablet once a day, or as one 
2 mg tablet taken twice a day. 
 
After about 8 weeks your doctor may need to increase your dose. The maximum dose is 8 mg of 
Avandia a day. 
 
How to take 
Swallow the tablets with some water. You can take Avandia with or without food. 

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55 

 
Take your tablets around the same time every day and follow any dietary advice that your doctor has 
given you. 
 
If you take more Avandia than you should  
If you accidentally take too many tablets, contact your doctor or pharmacist for advice.  
 
If you forget to take Avandia 
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 Avandia 
Take Avandia for as long as your doctor recommends. If you stop taking Avandia, 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, Avandia 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 Avandia. 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 Avandia. 

 
Fluid retention and heart failure: Avandia 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 Avandia 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 Avandia 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 
• loss of appetite 
• dark-coloured urine.  

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

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56 

 
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 Avandia 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 Avandia for more than one year. The most common 
are breaks in feet, hands and arms. 
 
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  
• constipation 
• swelling (oedema) due to water retention. 

 
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 
• rapid and excessive weight gain caused by fluid retention. 

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 AVANDIA 
 
Keep out of the reach and sight of children.  
 
Do not use Avandia after the expiry date shown on the pack. 
 
This medicine does not require any special storage conditions. 
 
If you have any unwanted tablets, don’t put them in waste water or household rubbish. Ask your 
pharmacist how to dispose of tablets you don’t need. This will help to protect the environment. 
 
 

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57 

6. FURTHER INFORMATION 
 
What Avandia contains 
The active substance is rosiglitazone. Avandia tablets come in different strengths.  Each tablet contains 
either: 2 mg, 4 mg or 8 mg rosiglitazone. 
 
The other ingredients are: sodium starch glycollate (Type A), hypromellose, hypromellose 6cP, 
microcrystalline cellulose, lactose monohydrate, magnesium stearate, titanium dioxide (E171), 
macrogol 3000, glycerol triacetate and iron oxide red (E172). The 4 mg tablet also contains purified 
talc and iron oxide yellow (E172). 
 
What Avandia looks like and contents of the pack 
Avandia 2 mg tablets are pink and marked "GSK" on one side and "2" on the other. The tablets are 
provided in blister packs containing 56, 112, 168 or 180 film-coated tablets or 56 film-coated tablets in 
a unit dose pack. 
Avandia 4 mg tablets are orange, marked "GSK" on one side and "4" on the other. The tablets are 
provided in blister packs containing 7, 28, 56, 84, 90 or 112 film-coated tablets or 56 film-coated 
tablets in a unit dose pack. 
Avandia 8 mg tablets are red-brown, marked "GSK" on one side and "8" on the other. The tablets are 
provided in blister packs containing 7, 28, 84, 90 or 112 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 Production, ZI du Terras, 53100 Mayenne, France. 
 
or 
 
Glaxo Wellcome S.A., Avenida de Extremadura 3, 09400 Aranda de Duero, Burgos, Spain. 

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58 

For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder. 
 
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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59 

 
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 
 
 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH RELEASE 
	B. CONDITIONS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET
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not be suitable for you. conditions to look out for avandia 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 avandia, 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 avandia. 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). 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: 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{'Title': '3. how to take avandia', 'Section_Content': "always take avandia 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 4 mg a day. this can be taken as one 4 mg tablet once a day, or as one 2 mg tablet taken twice a day. after about 8 weeks your doctor may need to increase your dose. the maximum dose is 8 mg of avandia a day. how to take swallow the tablets with some water. you can take avandia with or without food. take your tablets around the same time every day and follow any dietary advice that your doctor has given you. if you take more avandia than you should if you accidentally take too many tablets, contact your doctor or pharmacist for advice. if you forget to take avandia 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 avandia take avandia for as long as your doctor recommends. if you stop taking avandia, your blood sugar will not be controlled, and you may become unwell. talk to your doctor if you want to stop.", 'Entity_Recognition': [{'Text': 'avandia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'avandia tablets', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 27}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 211, 'EndOffset': 212}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 248, 'EndOffset': 249}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 282, 'EndOffset': 283}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 325, 'EndOffset': 326}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 397, 'EndOffset': 398}, {'Id': 12, 'BeginOffset': 405, 'EndOffset': 412, 'Score': 0.9951961636543274, 'Text': 'avandia', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9965170621871948, 'RelationshipScore': 0.9999518394470215, 'RelationshipType': 'DOSAGE', 'Id': 11, 'BeginOffset': 397, 'EndOffset': 401, 'Text': '8 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FREQUENCY', 'Score': 0.9602112174034119, 'RelationshipScore': 0.9998446702957153, 'RelationshipType': 'FREQUENCY', 'Id': 13, 'BeginOffset': 413, 'EndOffset': 418, 'Text': 'a day', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 14, 'BeginOffset': 482, 'EndOffset': 489, 'Score': 0.9943901896476746, 'Text': 'avandia', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'your tablets', 'Type': 'TREATMENT', 'BeginOffset': 517, 'EndOffset': 529}, {'Id': 15, 'BeginOffset': 640, 'EndOffset': 647, 'Score': 0.989625871181488, 'Text': 'avandia', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 16, 'BeginOffset': 775, 'EndOffset': 782, 'Score': 0.9939804077148438, 'Text': 'avandia', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.5485574007034302, 'RelationshipScore': 0.9998952150344849, 'RelationshipType': 'FORM', 'Id': 17, 'BeginOffset': 800, 'EndOffset': 807, 'Text': 'tablets', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'extra tablets', 'Type': 'TREATMENT', 'BeginOffset': 794, 'EndOffset': 807}, {'Id': 18, 'BeginOffset': 900, 'EndOffset': 907, 'Score': 0.9945717453956604, 'Text': 'avandia', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.7919592261314392}]}, {'Id': 19, 'BeginOffset': 913, 'EndOffset': 920, 'Score': 0.9968364238739014, 'Text': 'avandia', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.6248295307159424}]}, {'Id': 20, 'BeginOffset': 979, 'EndOffset': 986, 'Score': 0.9961857199668884, 'Text': 'avandia', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.6134746074676514}]}, {'Text': 'your blood sugar', 'Type': 'TEST', 'BeginOffset': 988, 'EndOffset': 1004}, {'Text': 'unwell', 'Type': 'PROBLEM', 'BeginOffset': 1048, 'EndOffset': 1054}]}
{'Title': '4. possible side effects', 'Section_Content': "like all medicines, avandia 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 avandia. 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 avandia. fluid retention and heart failure: avandia 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 avandia 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 avandia 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 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 avandia 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 avandia for more than one year. the most common are breaks in feet, hands and arms. 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 constipation swelling (oedema) due to water retention. rare side effects these may affect up to 1 in 1,000 people: fluid in the lungs (pulmonary oedema) causing 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{'Title': '5 how to store avandia', 'Section_Content': "keep out of the reach and sight of children. do not use avandia after the expiry date shown on the pack. 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.", 'Entity_Recognition': [{'Text': 'avandia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 56, 'EndOffset': 63, 'Score': 0.9857062101364136, 'Text': 'avandia', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.5203818082809448}]}]}
{'Title': '6. further information', 'Section_Content': 'what avandia contains the active substance is rosiglitazone. avandia tablets come in different strengths. each tablet contains either: 2 mg, 4 mg or 8 mg rosiglitazone. the other ingredients are: sodium starch glycollate (type a), hypromellose, hypromellose 6cp, microcrystalline cellulose, lactose monohydrate, magnesium stearate, titanium dioxide (e171), macrogol 3000, glycerol triacetate and iron oxide red (e172). the 4 mg tablet also contains purified talc and iron oxide yellow (e172). what avandia looks like and contents of the pack avandia 2 mg tablets are pink and marked "gsk" on one side and "2" on the other. the tablets are provided in blister packs containing 56, 112, 168 or 180 film-coated tablets or 56 film-coated tablets in a unit dose pack. avandia 4 mg tablets are orange, marked "gsk" on one side and "4" on the other. the tablets are provided in blister packs containing 7, 28, 56, 84, 90 or 112 film-coated tablets or 56 film-coated tablets in a unit dose pack. avandia 8 mg tablets are red-brown, marked "gsk" on one side and "8" on the other. the tablets are provided in blister packs containing 7, 28, 84, 90 or 112 film-coated tablets. not all pack sizes or tablet strengths may be available in your country.', 'Entity_Recognition': [{'Text': 'avandia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'what avandia', 'Type': 'PROBLEM', 'BeginOffset': 0, 'EndOffset': 12}, {'Id': 1, 'BeginOffset': 46, 'EndOffset': 59, 'Score': 0.9980383515357971, 'Text': 'rosiglitazone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.9052489399909973, 'RelationshipScore': 0.7656779885292053, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 69, 'EndOffset': 76, 'Text': 'tablets', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'avandia tablets', 'Type': 'TREATMENT', 'BeginOffset': 61, 'EndOffset': 76}, {'Text': '2', 'Type': 'NUMBER', 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