Avaglim

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1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 

 



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1. NAME OF THE MEDICINAL PRODUCT 
 
AVAGLIM 4 mg/4 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains rosiglitazone maleate corresponding to 4 mg rosiglitazone and 4 mg glimepiride. 
 
Excipient 
- contains lactose (approximately 104 mg) 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Pink, rounded triangular tablet with “gsk” debossed on one side and “4/4” on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
AVAGLIM is indicated in the treatment of type 2 diabetes mellitus patients who are unable to achieve 
sufficient glycaemic control on optimal dosage of sulphonylurea monotherapy, and for whom 
metformin is inappropriate because of contraindication or intolerance. 
 
4.2 Posology and method of administration 
 
AVAGLIM therapy should be individualised for each patient. Before therapy is initiated with 
AVAGLIM appropriate clinical evaluation should be made to assess the patient’s risk of developing 
hypoglycaemia (see section 4.4). 
 
AVAGLIM should be taken once daily shortly before or during a meal (usually the first main meal of 
the day). If a dose is forgotten, the following dose must not be increased. 
 
For patients inadequately controlled on glimepiride monotherapy (typically 4 mg). Concomitant 
administration should be considered before the patient is switched to AVAGLIM. Where clinically 
appropriate, direct change from glimepiride monotherapy to AVAGLIM may be considered. The 
starting dose is 4 mg/day rosiglitazone plus 4 mg/day glimepiride (given as one tablet AVAGLIM 
4 mg/4 mg). 
 
Patients unable to achieve glycaemic control on at least half-maximum dose of other sulphonylurea 
monotherapy (except chlorpropamide, see section 4.4). Rosiglitazone 4 mg should be administered 
concomitantly with the dose of sulphonylurea already being taken. Once glycaemic control is stable at 
these doses, AVAGLIM may be introduced at a starting dose of 4 mg rosiglitazone/4 mg glimepiride 
once daily.  
 
AVAGLIM may be used to substitute concomitant sulphonylurea and rosiglitazone in established dual 
oral therapy providing the patient has achieved at least half-maximum dose of sulphonylurea.  
 
The dose of the rosiglitazone component can be increased after 8 weeks if required. The maximum 
recommended daily dose is 8 mg rosiglitazone/4 mg glimepiride (given as one AVAGLIM tablet 
8 mg/4 mg, once daily). An increase in the rosiglitazone component to 8 mg/day should be undertaken 



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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). 
 
If hypoglycaemic symptoms occur, the patient should revert to concomitant therapy and adjust the 
glimepiride dose as appropriate. 
 
Elderly  
Due to the potential for decreased renal function the initiation and maintenance of therapy with 
AVAGLIM in elderly patients should be under close medical supervision due to an increased 
susceptibility to hypoglycaemia (see section 4.4). 
 
Patients with renal impairment  
Mild or moderate renal impairment (creatinine clearance 30 to 80 ml/min):  
- Patients changing to AVAGLIM from sulphonylurea therapies other than glimepiride may be at 

an increased risk of hypoglycaemia (see section 4.4). Appropriate monitoring is advised. 
AVAGLIM is contraindicated in patients with severe renal impairment (creatinine clearance less than 
30 ml/min, see section 4.3).  
 
Patients with hepatic impairment 
AVAGLIM is contraindicated in patients with hepatic impairment (see section 4.3). 
 
Children and adolescents  
AVAGLIM is not recommended for use in children below 18 years of age as there are no data 
available on its safety and efficacy. 
 
4.3 Contraindications 
 
Use of AVAGLIM is contraindicated in patients with: 
 
− hypersensitivity to rosiglitazone, glimepiride, other sulphonylureas or sulphonamides 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 
− severe renal impairment i.e. creatinine clearance less than 30 ml/min (including renal dialysis). 
− insulin dependant diabetes 
− diabetic ketoacidosis or diabetic coma. 
 
 
4.4 Special warnings and precautions for use 
 
AVAGLIM is not indicated for combination use with metformin and therefore should not be used in 
triple oral therapy of diabetes. 
 
The following statements refer to AVAGLIM or the two individual active substances (rosiglitazone 
and glimepiride). 
  
Hypoglycaemia 
Patients receiving AVAGLIM may be at risk of dose-related hypoglycaemia (see section 4.8). It is 
advised that patients established on rosiglitazone and chlorpropamide concomitant therapy should not 
switch to AVAGLIM as chlorpropamide has a long half-life which may increase the risk of 
hypoglycaemia. If risk factors for hypoglycaemia are present (including renal insufficiency, low body 
weight, malnourishment, co-administration with certain other medicinal products (see section 4.5) or if 
the patient’s life-style changes) it may be necessary to revert to concomitant therapy and down titrate 
the glimepiride dose. A switch to insulin should be considered in stress situations (e.g. trauma, 
surgery, infections). 
 



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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 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. 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, 
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 with 
rosiglitazone (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 AVAGLIM in all patients and periodically thereafter based on clinical 
judgement. Therapy with AVAGLIM 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 AVAGLIM 
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 



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oedema if patients report disturbances in visual acuity and appropriate ophthalmologic referral should 
be considered. 
 
Patients with renal impairment 
Patients with mild or moderate renal impairment (creatinine clearance 30 to 80 ml/min) may be at an 
increased risk of hypoglycaemia (see sections 4.2, 4.3 and 4.4). Appropriate monitoring is advised. 
 
Premenopausal anovulatory women 
Premenopausal women have received rosiglitazone during clinical studies. Although hormonal 
imbalance has been seen in preclinical studies (see section 5.3), no significant undesirable effects 
associated with menstrual disorders have been observed. As a consequence of improving insulin 
sensitivity, resumption of ovulation may occur in patients who are anovulatory due to insulin 
resistance. Patients should be aware of the risk of pregnancy (see section 4.6). 
 
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. 
 
Haematological monitoring 
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 AVAGLIM. 
 
Periodic haematological monitoring (especially leucocytes and thrombocytes) are required during 
treatment with AVAGLIM. 
 
Treatment of patients with G6PD-deficiency with sulphonylurea agents can lead to haemolytic 
anaemia. Since glimepiride belongs to the chemical class of sulphonylurea drugs, caution should be 
used in patients with G6PD-deficiency and a non-sulphonylurea alternative should be considered. 
 
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. 
 
Administration with other medicinal products 
Rosiglitazone should be used with caution during concomitant administration of CYP2C8 inhibitors 
(e.g. gemfibrozil) or inducers (e.g. rifampicin). Glimepiride should be used with caution during 
concomitant administration of CYP2C9 inhibitors (e.g. fluconazole) or inducers (see section 4.5). 
Glycaemic control should be monitored closely. AVAGLIM dose adjustment within the recommended 
posology or changes in diabetic treatment should be considered. 
 
Lactose intolerance 
AVAGLIM tablets contain lactose and therefore should not be administered to patients with rare 
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose 
malabsorption. 
 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
There have been no formal interaction studies for AVAGLIM. However, the concomitant use of the 
active substances in patients in clinical studies and in widespread clinical use has not resulted in any 
unexpected interactions. The following statements reflect the information available on the individual 
active substances (rosiglitazone and glimepiride). 



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Rosiglitazone 
In vitro studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with 
CYP2C9 as only a minor pathway.  
 
Clinically significant interactions with CYP2C9 substrates or inhibitors are not anticipated. 
 
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). 
 
Concomitant administration of rosiglitazone with the oral anti-diabetic agents metformin, glimepiride, 
glibenclamide and acarbose did not result in any clinically relevant pharmacokinetic interactions.  
 
No clinically relevant interactions with digoxin, the CYP2C9 substrate warfarin, the CYP3A4 
substrates nifedipine, ethinylestradiol or norethindrone were observed after co-administration with 
rosiglitazone. 
 
Glimepiride 
If glimepiride is taken simultaneously with certain other medicines, both undesired increases and 
decreases in the hypoglycaemic action of glimepiride can occur. For this reason, other medicines 
should only be taken with the knowledge (or at the prescription) of the doctor. 
 
Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). Its metabolism is known to be 
influenced by concomitant administration of CYP2C9 inducers (e.g. rifampicin) or inhibitors (e.g. 
fluconazole 
 
Results from an vivo interaction study reported in literature show that glimepiride AUC is increased 
approximately 2-fold by fluconazole, one of the most potent CYP2C9 inhibitors. 
 
Based on the experience with glimepiride and with other sulphonylureas the following interactions 
have to be mentioned. 
 
Potentiation of the blood-glucose-lowering effect and, thus, in some instances hypoglycaemia may 
occur when one of the following drugs is taken, for example: 
 
phenylbutazone, azapropazon and oxyfenbutazone, sulphinpyrazone, 
insulin and oral antidiabetic products,   certain long acting sulphonamides, 
metformin,     tetracyclines, 
salicylates and p-amino-salicylic acid,   MAO-inhibitors, 
anabolic steroids and male sex hormones,  quinolone antibiotics, 
chloramphenicol,     probenecid, 
coumarin anticoagulants,    miconazol, 
fenfluramine,     pentoxifylline (high dose parenteral), 
fibrates,      tritoqualine, 
ACE inhibitors,     fluconazole. 
fluoxetine,  
allopurinol, 
sympatholytics, 
cyclo-, tro-and iphosphamides, 



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Weakening of the blood-glucose-lowering effect and, thus raised blood glucose levels may occur when 
one of the following drugs is taken, for example: 
 
oestrogens and progestagens,  
saluretics, thiazide diuretics, 
thyroid stimulating agents, glucocorticoids, 
phenothiazine derivatives, chlorpromazine, 
adrenaline and sympathicomimetics,  
nicotinic acid (high dosages) and nicotinic acid derivatives, 
laxatives (long term use), 
phenytoin, diazoxide, 
glucagon, barbiturates and rifampicin, 
acetozolamide. 
 
H2 antagonists, betablockers, clonidine and reserpine may lead to either potentiation or weakening of 
the blood glucose lowering effect.  
 
Under the influence of sympatholytic drugs such as betablockers, clonidine, guanethidine and 
reserpine, the signs of adrenergic counterregulation to hypoglycaemia may be reduced or absent. 
 
Alcohol intake may potentiate or weaken the hypoglycaemic action of glimepiride in an unpredictable 
fashion.  
 
Glimepiride may either potentiate or weaken the effects of coumarin derivatives. 
 
4.6 Pregnancy and lactation 
 
For AVAGLIM no preclinical or clinical data on exposed pregnancies or lactation are available. 
 
Rosiglitazone has been reported to cross the human placenta and to be detectable in foetal tissues. 
There are no adequate data from the use of either active substance (rosiglitazone and glimepiride) in 
pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential 
risk for humans is unknown.  
 
Therefore, AVAGLIM should not be used during pregnancy and the use of insulin is recommended. If 
a patient wishes to become pregnant or if pregnancy occurs, treatment with AVAGLIM should be 
discontinued. 
 
Both rosiglitazone and glimepiride have been detected in the milk of experimental animals. It is not 
known whether breast-feeding will lead to exposure of the infant to medicinal product. Therefore, 
AVAGLIM should not be used during lactation.  
 
4.7 Effects on ability to drive and use machines 
 
No studies of the effects on the ability to drive and use machines have been performed. Nevertheless, 
the potential for hypoglycaemia should be borne in mind when considering the patient's ability to 
perform tasks that require judgement, motor or cognitive skills (e.g. driving).  
 
4.8 Undesirable effects 
 
Adverse reactions are presented below for each of the component parts of AVAGLIM. An adverse 
reaction is only presented for the fixed dose combination if it has not been seen in one of the 
component parts of AVAGLIM or if it occurred at a higher frequency than that listed for a component 
part. 
 
 



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AVAGLIM 
Data from double-blind studies confirm that the safety profile of concomitant rosiglitazone and 
glimepiride is similar to that of the combined adverse reaction profile for the two active substances. 
Limited data with AVAGLIM is also consistent with this combined adverse reaction profile. 
 
Rosiglitazone 
 
Clinical trial data 
Adverse reactions for each treatment regimen are presented below by system organ class and absolute 
frequency. For dose-related adverse reactions the frequency category reflects the higher dose of 
rosiglitazone. Frequency categories do not account for other factors including varying study duration, 
pre-existing conditions and baseline patient characteristics. 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 with rosiglitazone 
 
Adverse reaction Frequency of adverse reaction by treatment regimen 
 Rosiglitazone monotherapy Rosiglitazone with 

sulphonylurea 
 
Blood and the lymphatic system disorders 
anaemia Common Common 
leucopaenia  Common 
thrombocytopaenia  Common 
 
Metabolism and nutrition disorders 
hypercholesterolaemia1 Common Common 
hypertriglyceridaemia Common Common 
hyperlipaemia Common Common 
weight increase Common Common 
increased appetite Common Uncommon 
hypoglycaemia  Very common 
 
Nervous system disorders 
dizziness*  Common 
 
Cardiac disorders 
cardiac failure2  Common 
cardiac ischaemia3* Common Common 
 
Gastrointestinal disorders 
constipation Common Common 
 
Musculoskeletal and connective tissue disorders 
bone fractures4 Common Common 
 
General disorders and administration site conditions 
oedema Common Very common 
 



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*The frequency category for the background incidence of this event, 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 or dual 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 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 
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. 
 
 



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Table 2. The frequency of adverse reactions identified from post-marketing data with 
rosiglitazone 
 
Adverse reaction Frequency 
 
Metabolism and nutrition disorders 
rapid and excessive weight gain Very rare 
 
Immune system disorders (see Skin and subcutaneous tissue disorders) 
anaphylactic reaction Very rare 
 
Eye disorders 
macular oedema Rare 
 
Cardiac disorders 
congestive heart failure/pulmonary oedema Rare 
 
Hepatobiliary disorders 
hepatic dysfunction, primarily evidenced by elevated hepatic enzymes5 Rare 
 
Skin and subcutaneous tissue disorders (see Immune system disorders) 
angioedema Very rare 
skin reactions (e.g. urticaria, pruritis, rash) Very rare 

 
5 Rare cases of elevated liver enzymes and hepatocellular dysfunction have been reported. In very rare 
cases a fatal outcome has been reported. 
 
Glimepiride 
 
Clinical trial data and post-marketing data 
Table 3 presents adverse reactions by system organ class and by frequency category based on 
experience with glimepiride and other sulphonylureas. Frequencies are defined as: very common 
(≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥1/10,000, <1/1000) and 
very rare (<1/10,000 including isolated reports). 
 
Table 3. The frequency of glimepiride adverse reactions identified from clinical trial and post-
marketing data  
 
Adverse reaction Frequency 
 
Blood and lymphatic system disorders 
agranulocytosis Rare 
granulocytopenia Rare 
pancytopenia Rare 
haemolytic anaemia Rare 
thrombocytopenia Rare 
leukopenia Rare 
erythrocytopenia Rare 
 
Immune system disorders6 
allergic vasculitis Very rare 
hypersensitivity reactions7 Very rare 
 
Metabolism and nutrition disorders 
hypoglycaemia8 Very common 



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Gastrointestinal disorders 
vomiting Very rare 
diarrhoea Very rare 
nausea Very rare 
abdominal distension Very rare 
abdominal pain Very rare 
abdominal discomfort Very rare 
 
Hepatobiliary disorders9 
hepatitis10 Very rare 
impairment of liver function (e.g. with cholestasis and jaundice) Very rare 
 
Skin and subcutaneous tissue disorders11 
hypersensitivity of the skin to light  Very rare 
 
Investigations 
serum sodium decrease Very rare 
 
6 Cross-allergenicity with sulphonylureas, sulphonamides or related substances is possible. 
7 Mild hypersensitivity reactions may develop into serious reactions with dyspnoea, fall in blood 
pressure and sometimes shock.  
 
8 Based on what is known of other sulphonylureas, hypoglycaemia may be prolonged. Rarely 
hypoglycaemic reactions can occur immediately and may be severe and not always easy to correct. 
 
9 Elevation of liver enzymes may occur. 
10 Hepatitis  may progress to liver failure. 
 
11 Hypersensitivity reactions of the skin may occur as itching, rash and urticaria. 
 
Transient visual disturbances may occur especially on initiation of treatment, due to changes in blood 
glucose levels. 
 
4.9 Overdose 
 
No data are available with regard to overdose of AVAGLIM. 
 
Limited data are available with regard to overdose of rosiglitazone in humans. In clinical studies in 
volunteers rosiglitazone has been administered at single oral doses of up to 20 mg and was well 
tolerated. 
 
Overdose of sulphonylureas, including glimepiride, can result in severe life-threatening 
hypoglycaemia lasting 12 to 72 hours, which may recur after apparent recovery. The symptoms may 
be delayed for up to 24 hours after ingestion. Hospitalisation should be considered as appropriate. 
 
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 and glimepiride are both highly 
protein bound and would not be expected to be cleared by haemodialysis. 
 
 
 
 
 
 
 



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5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Combinations of oral blood glucose lowering drugs, ATC code: 
A10BD04. 
 
AVAGLIM combines two antidiabetic agents with complimentary mechanisms of action to improve 
glycaemic control in patients with type 2 diabetes: rosiglitazone maleate, a member of the 
thiazolidinedione class and glimepiride, a member of the sulphonylurea class. Thiazolidinediones act 
primarily by reducing insulin resistance and sulphonylureas act primarily by stimulating release of 
insulin from functioning pancreatic β-cells. A study comparing AVAGLIM to monotherapy 
rosiglitazone or glimepiride demonstrated incremental benefit in control of glycaemia of the 
fixed-dose combination over monotherapy.  No new safety findings were observed. The clinical trial 
program in support of this fixed dose combination only compared rosiglitazone and glimepiride to 
glimepiride monotherapy and not to monotherapy with other sulphonylureas. 
 
Rosiglitazone 
Rosiglitazone is a selective agonist at the PPARγ (peroxisome proliferator activated receptor gamma) 
nuclear receptor and is a member of the thiazolidinedione class of antihyperglycaemic agents. It 
reduces glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver. 
 
The antihyperglycaemic activity of rosiglitazone has been demonstrated in a number of animal models 
of type 2 diabetes. In addition, rosiglitazone preserved ß-cell function as shown by increased 
pancreatic islet mass and insulin content and prevented the development of overt hyperglycaemia in 
animal models of type 2 diabetes. Rosiglitazone did not stimulate pancreatic insulin secretion or 
induce hypoglycaemia in rats and mice. The major metabolite (a para-hydroxy-sulphate) with high 
affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in 
obese mice. The clinical relevance of this observation has not been fully elucidated. 
 
In clinical trials, the glucose lowering effects observed with rosiglitazone are gradual in onset with 
near maximal reductions in fasting plasma glucose (FPG) evident following approximately 8 weeks of 
therapy. The improved glycaemic control is associated with reductions in both fasting and post-
prandial glucose. 
 
Rosiglitazone was associated with increases in weight. In mechanistic studies, the weight increase was 
predominantly shown to be due to increased subcutaneous fat with decreased visceral and intra-hepatic 
fat. 
 
Consistent with the mechanism of action, rosiglitazone 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. 
 
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, 



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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). 
 
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. 
 
Glimepiride 
Glimepiride is an orally active hypoglycaemic substance belonging to the sulphonylurea group. It may 
be used in non-insulin dependent diabetes mellitus. 
Glimepiride acts mainly by stimulating the release of insulin from the beta cells of the pancreas. As 
with other sulphonylureas, this effect is based on an improvement in responsiveness of pancreatic beta 
cells to the physiological glucose stimulus. In addition, glimepiride seems to have pronounced 
extrapancreatic effects, also postulated for other sulphonylureas. 
 



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Sulphonylureas regulate insulin secretion by closing the ATP-dependent potassium channels in the 
beta cell membrane. Closure of the potassium channels leads to depolarisation of the beta cell and 
results by opening of the calcium channels – to an increased influx of calcium into the cell. This leads 
to a release of insulin by exocytosis. 
 
Glimepiride binds with a high exchange rate to a beta cell membrane protein which is associated with 
the ATP-sensitive potassium channel but which differs from the usual sulphonylurea binding site. 
 
Extrapancreatic effects include an improvement in insulin sensitivity of peripheral tissue and a 
reduction in hepatic uptake of insulin. 
Glimepiride very rapidly increases the number of active glucose transport molecules in the plasma 
membranes of muscle and fat cells, resulting in stimulation of glucose uptake. 
Glimepiride increases the activity of glycosyl-phosphatidylinositol-specific phospholipase C, which 
may be associated with drug-induced lipogenesis and glycogenesis in isolated fat and muscle cells. 
Glimepiride inhibits the hepatic glucose production by increasing the intracellular concentration of 
fructose-2,6 bisphosphate, which in turn inhibits gluconeogenesis. 
 
The minimum effective oral dose is approximately 0.6 mg. The effect of glimepiride is dose-
dependent and reproducible. The physiological response to acute physical exercise, a reduction in 
insulin secretion, is maintained during treatment with glimepiride. 
There was no significant difference in the effect regardless of whether the drug was taken 30 minutes 
before or immediately before a meal. In diabetic patients, good metabolic control over 24 hours can be 
achieved with a single daily dose. 
Although the hydroxy metabolite of glimepiride caused a small but significant reduction in serum 
glucose, it accounts for only a minor part of the total drug effect. 
 
5.2 Pharmacokinetic properties 
 
AVAGLIM 
 
Single oral doses of glimepiride in 14 healthy adult subjects had no clinically significant effect on the 
steady-state pharmacokinetics of rosiglitazone. No clinically significant reductions in glimepiride 
AUC and Cmax were observed after repeat doses of rosiglitazone for eight days in healthy adult 
subjects.  
 
In a bioequivalence study under fasted conditions, the AUC and Cmax of rosiglitazone and the AUC of 
glimepiride following a single dose of a 4 mg/4 mg combination tablet were bioequivalent to 
concomitant administration of rosiglitazone 4 mg and glimepiride 4 mg. 
 
In the fed state, the rate and extent of absorption of the rosiglitazone-glimepiride 4 mg/4 mg 
combination were equivalent to concomitant administration of 4 mg rosiglitazone and 4 mg 
glimepiride. Administration of the 4 mg/4 mg combination with food led to an increase in glimepiride 
exposure compared to that observed on administration in the fasted state. Glimepiride AUC0-t, AUC0-inf 
and Cmax were increased by 30%, 19% and 55% respectively, on average. For rosiglitazone, Cmax 
values were decreased by approximately 32% with food. 
 
The AUC and Cmax of glimepiride increased in a dose-proportional manner following administration of 
rosiglitazone-glimepiride 4 mg/1 mg, 4 mg/2 mg, and 4 mg/4 mg.  
 
The following statements reflect the pharmacokinetic properties of the individual components of 
AVAGLIM. 
 
Rosiglitazone 
Absorption 
Absolute bioavailability of rosiglitazone following both a 4 and an 8 mg oral dose is approximately 
99%. Rosiglitazone plasma concentrations peak at around 1 h after dosing. Plasma concentrations are 
approximately dose proportional over the therapeutic dose range. 



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Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), although a 
small decrease in Cmax (approximately 20-28%) and a delay in tmax (approximately 1.75 h) were 
observed compared to dosing in the fasted state. These small changes are not clinically significant and, 
therefore, it is not necessary to administer rosiglitazone at any particular time in relation to meals. The 
absorption of rosiglitazone is not affected by increases in gastric pH. 
 
Distribution 
The volume of distribution of rosiglitazone is approximately 14 l in healthy volunteers. Plasma protein 
binding of rosiglitazone is high (approximately 99.8%) and is not influenced by concentration or age. 
The protein binding of the major metabolite (a para-hydroxy-sulphate) is very high (> 99.99%). 
 
Metabolism 
Metabolism of rosiglitazone is extensive with no parent compound being excreted unchanged. The 
major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with 
sulphate and glucuronic acid. The contribution of the major metabolite (a para-hydroxy-sulphate) to 
the overall antihyperglycaemic activity of rosiglitazone has not been fully elucidated in man and it 
cannot be ruled out that the metabolite may contribute to the activity. However, this raises no safety 
concern regarding target or special populations as hepatic impairment is contraindicated and the phase 
III clinical studies included a considerable number of elderly patients and patients with mild to 
moderate renal impairment. 
 
In vitro studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor 
contribution by CYP2C9. 
Since there is no significant in vitro inhibition of CYP1A2, 2A6, 2C19, 2D6, 2E1, 3A or 4A with 
rosiglitazone, there is a low probability of significant metabolism-based interactions with substances 
metabolised by these P450 enzymes. Rosiglitazone showed moderate inhibition of CYP2C8 
(IC50 18 µM) and low inhibition of CYP2C9 (IC50 50 µM) in vitro (see section 4.5). An in vivo 
interaction study with warfarin indicated that rosiglitazone does not interact with CYP2C9 substrates 
in vivo. 
 
Elimination 
Total plasma clearance of rosiglitazone is around 3 l/h and the terminal elimination half-life of 
rosiglitazone is approximately 3-4 h. There is no evidence for unexpected accumulation of 
rosiglitazone after once or twice daily dosing. The major route of excretion is the urine with 
approximately two-thirds of the dose being eliminated by this route, whereas faecal elimination 
accounts for approximately 25% of dose. No intact active substance is excreted in urine or faeces. The 
terminal half-life for radioactivity was about 130 h indicating that elimination of metabolites is very 
slow. Accumulation of the metabolites in plasma is expected upon repeated dosing, especially that of 
the major metabolite (a para-hydroxy-sulphate) for which an 8-fold accumulation is anticipated. 
 
Glimepiride 
Absorption 
After oral administration, glimepiride is completely (100%) absorbed from the gastrointestinal tract. 
Studies with single oral doses in normal subjects and with multiple oral doses in patients with type 2 
diabetes mellitus have shown significant absorption of glimepiride within 1 h after administration and 
Cmax at approximately 2.5 h. There is a linear relationship between dose and both Cmax and AUC. 
 
Distribution 
After intravenous dosing in normal subjects, the volume of distribution was 8.8 l (113 ml/kg), and the 
total body clearance was 47.8 ml/min. Protein binding was greater than 99.5%. 
 
Metabolism 
Glimepiride is completely metabolised by oxidative biotransformation after either an intravenous or 
oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl 
derivative (M2). CYP2C9 has been shown to be involved in the biotransformation of glimepiride to 
M1. M1 is further metabolised to M2 by one or several cytosolic enzymes. M1, but not M2, possesses 



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about 1/3 of the pharmacological activity as compared to its parent in an animal model. The clinical 
significance of the glucose-lowering effect of M1 is unclear. 
 
Elimination 
The elimination half-life of glimepiride is approximately 5 to 8 h. When 14C-glimepiride was given 
orally, approximately 60% of the total radioactivity was recovered in the urine in seven days and M1 
(predominant) and M2 accounted for 80 to 90% of that recovered in the urine. Approximately 40% of 
the total radioactivity was recovered in faeces and M1 and M2 (predominant) accounted for about 70% 
of that recovered in faeces. No parent drug was recovered from urine or faeces. After intravenous 
dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite was observed. 
 
 
Special populations 
Gender: In the pooled population pharmacokinetic analysis, there were no marked differences in the 
pharmacokinetics of rosiglitazone or glimepiride between males and females. 
 
Elderly: In the pooled population pharmacokinetic analysis, age was not found to influence the 
pharmacokinetics of rosiglitazone or glimepiride to any significant extent. 
 
Hepatic impairment: Following rosiglitazone treatment 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. No adequate pharmacokinetic studies of glimepiride have been conducted in subjects with 
functional hepatic impairment. Therefore AVAGLIM should not be used in patients with hepatic 
impairment (see section 4.3) 
 
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. There 
are no data from the use of glimepiride in patients on renal dialysis (see section 4.3). 
 
A multiple-dose titration study with glimepiride conducted in 16 patients with type 2 diabetes mellitus 
with renal impairment using doses ranging from 1 to 8 mg daily for three months showed that all 
patients with a creatinine clearance less than 22 ml/min had adequate control of their glucose levels 
with a dosage regimen of only 1 mg daily (see section 4.2 and 4.4). 
 
5.3 Preclinical safety data 
 
No animal studies have been conducted with the combined products in AVAGLIM. The following 
data are findings in studies performed with rosiglitazone or glimepiride individually. 
 
Rosiglitazone 
Undesirable effects observed in animal studies with possible relevance to clinical use were as follows: 
An increase in plasma volume accompanied by decrease in red cell parameters and increase in heart 
weight. Increases in liver weight, plasma ALT (dog only) and fat tissue were also observed.  Similar 
effects have been seen with other thiazolidinediones. 
 
In reproductive toxicity studies, administration of rosiglitazone to rats during mid-late gestation was 
associated with foetal death and retarded foetal development. In addition, rosiglitazone inhibited 
ovarian oestradiol and progesterone synthesis and lowered plasma levels of these hormones resulting 
in effects on oestrus/menstrual cycles and fertility (see section 4.4). 
 
In an animal model for familial adenomatous polyposis (FAP), treatment with rosiglitazone at 200 
times the pharmacologically active dose increased tumour multiplicity in the colon. The relevance of 
this finding is unknown. However, rosiglitazone promoted differentiation and reversal of mutagenic 
changes in human colon cancer cells in vitro. In addition, rosiglitazone was not genotoxic in a battery 
of in vivo and in vitro genotoxicity studies and there was no evidence of colon tumours in lifetime 
studies of rosiglitazone in two rodent species. 



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Glimepiride 
 Preclinical effects were observed only at exposures considered sufficiently in excess of the maximum 
human exposure indicating little relevance to clinical use or were caused by the pharmacodynamic 
effect (hypoglycaemia) of the substance. This was based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and fertility. Studies on 
embryofoetal development and pre-and postnatal development revealed eye malformations, skeletal 
anomalies, abortions, and an increased foetal death rate. 
Reproduction toxicology findings may be related to the pharmacodynamic action of glimepiride. 
Glimepiride is excreted into the milk of lactating rats. High doses given to mother rats cause 
hypoglycaemia in suckling young rats (see section 4.6). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
4/4 
Tablet core:  
Sodium starch glycolate Type A 
Hypromellose (E464) 
Microcrystalline cellulose (E460) 
Lactose monohydrate 
Magnesium stearate. 
 
Film coat: 
Hypromellose (E464) 
Titanium dioxide (E171) 
Macrogol 400 
Iron oxide black (E172) 
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 blisters (PVC/PVDC/aluminium). Packs of 14, 28, 56, 84 or 112 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 
 



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SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom. 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/349/001-004 
EU/1/06/349/009 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
27 June 2006 
 
 
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 
 
AVAGLIM 8 mg/4 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains rosiglitazone maleate corresponding to 8 mg rosiglitazone and 4 mg glimepiride. 
 
Excipient 
- contains lactose (approximately 235 mg) 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Red, biconvex, rounded triangular tablet with “gsk” debossed on one side and “8/4” on the other side 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
AVAGLIM is indicated in the treatment of type 2 diabetes mellitus patients who are unable to achieve 
sufficient glycaemic control on optimal dosage of sulphonylurea monotherapy, and for whom 
metformin is inappropriate because of contraindication or intolerance. 
 
4.2 Posology and method of administration 
 
AVAGLIM therapy should be individualised for each patient. Before therapy is initiated with 
AVAGLIM appropriate clinical evaluation should be made to assess the patient’s risk of developing 
hypoglycaemia (see section 4.4). 
 
AVAGLIM should be taken once daily shortly before or during a meal (usually the first main meal of 
the day). If a dose is forgotten, the following dose must not be increased. 
 
For patients inadequately controlled on glimepiride monotherapy (typically 4 mg). Concomitant 
administration should be considered before the patient is switched to AVAGLIM. Where clinically 
appropriate, direct change from glimepiride monotherapy to AVAGLIM may be considered. The 
starting dose is 4 mg/day rosiglitazone plus 4 mg/day glimepiride (given as one tablet AVAGLIM 
4 mg/4 mg). 
 
Patients unable to achieve glycaemic control on at least half-maximum dose of other sulphonylurea 
monotherapy (except chlorpropamide, see section 4.4). Rosiglitazone 4 mg should be administered 
concomitantly with the dose of sulphonylurea already being taken. Once glycaemic control is stable at 
these doses, AVAGLIM may be introduced at a starting dose of 4 mg rosiglitazone/4 mg glimepiride 
once daily.  
 
AVAGLIM may be used to substitute concomitant sulphonylurea and rosiglitazone in established dual 
oral therapy providing the patient has achieved at least half-maximum dose of sulphonylurea.  
 
The dose of the rosiglitazone component can be increased after 8 weeks if required. The maximum 
recommended daily dose is 8 mg rosiglitazone/4 mg glimepiride (given as one AVAGLIM tablet 
8 mg/4 mg, once daily). An increase in the rosiglitazone component to 8 mg/day should be undertaken 



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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). 
 
If hypoglycaemic symptoms occur, the patient should revert to concomitant therapy and adjust the 
glimepiride dose as appropriate. 
 
Elderly  
Due to the potential for decreased renal function the initiation and maintenance of therapy with 
AVAGLIM in elderly patients should be under close medical supervision due to an increased 
susceptibility to hypoglycaemia (see section 4.4). 
 
Patients with renal impairment  
Mild or moderate renal impairment (creatinine clearance 30 to 80 ml/min):  
-Patients changing to AVAGLIM from sulphonylurea therapies other than glimepiride may be at an 
increased risk of hypoglycaemia (see section 4.4). Appropriate monitoring is advised. 
AVAGLIM is contraindicated in patients with severe renal impairment (creatinine clearance less than 
30 ml/min, see section 4.3).  
 
Patients with hepatic impairment 
AVAGLIM is contraindicated in patients with hepatic impairment (see section 4.3). 
 
Children and adolescents  
AVAGLIM is not recommended for use in children below 18 years of age as there are no data 
available on its safety and efficacy. 
 
4.3 Contraindications 
 
Use of AVAGLIM is contraindicated in patients with: 
 
− hypersensitivity to rosiglitazone, glimepiride, other sulphonylureas or sulphonamides 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 
− severe renal impairment i.e. creatinine clearance less than 30 ml/min (including renal dialysis). 
− insulin dependant diabetes 
− diabetic ketoacidosis or diabetic coma. 
 
 
4.4 Special warnings and precautions for use 
 
AVAGLIM is not indicated for combination use with metformin and therefore should not be used in 
triple oral therapy of diabetes. 
 
The following statements refer to AVAGLIM or the two individual active substances (rosiglitazone 
and glimepiride). 
  
Hypoglycaemia 
Patients receiving AVAGLIM may be at risk of dose-related hypoglycaemia (see section 4.8). It is 
advised that patients established on rosiglitazone and chlorpropamide concomitant therapy should not 
switch to AVAGLIM as chlorpropamide has a long half-life which may increase the risk of 
hypoglycaemia. If risk factors for hypoglycaemia are present (including renal insufficiency, low body 
weight, malnourishment, co-administration with certain other medicinal products (see section 4.5) or if 
the patient’s life-style changes) it may be necessary to revert to concomitant therapy and down titrate 
the glimepiride dose. A switch to insulin should be considered in stress situations (e.g. trauma, 
surgery, infections). 
 



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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 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. 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, 
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 with 
rosiglitazone (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 AVAGLIM in all patients and periodically thereafter based on clinical 
judgement. Therapy with AVAGLIM 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 AVAGLIM 
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 



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oedema if patients report disturbances in visual acuity and appropriate ophthalmologic referral should 
be considered. 
 
Patients with renal impairment 
Patients with mild or moderate renal impairment (creatinine clearance 30 to 80 ml/min) may be at an 
increased risk of hypoglycaemia (see sections 4.2, 4.3 and 4.4). Appropriate monitoring is advised. 
 
Premenopausal anovulatory women 
Premenopausal women have received rosiglitazone during clinical studies. Although hormonal 
imbalance has been seen in preclinical studies (see section 5.3), no significant undesirable effects 
associated with menstrual disorders have been observed. As a consequence of improving insulin 
sensitivity, resumption of ovulation may occur in patients who are anovulatory due to insulin 
resistance. Patients should be aware of the risk of pregnancy (see section 4.6). 
 
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.  
 
Haematological monitoring 
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 AVAGLIM. 
 
Periodic haematological monitoring (especially leucocytes and thrombocytes) are required during 
treatment with AVAGLIM. 
 
Treatment of patients with G6PD-deficiency with sulphonylurea agents can lead to haemolytic 
anaemia. Since glimepiride belongs to the chemical class of sulphonylurea drugs, caution should be 
used in patients with G6PD-deficiency and a non-sulphonylurea alternative should be considered. 
 
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. 
 
Administration with other medicinal products 
Rosiglitazone should be used with caution during concomitant administration of CYP2C8 inhibitors 
(e.g. gemfibrozil) or inducers (e.g. rifampicin). Glimepiride should be used with caution during 
concomitant administration of CYP2C9 inhibitors (e.g. fluconazole) or inducers (see section 4.5). 
Glycaemic control should be monitored closely. AVAGLIM dose adjustment within the recommended 
posology or changes in diabetic treatment should be considered. 
 
Lactose intolerance 
AVAGLIM tablets contain lactose and therefore should not be administered to patients with rare 
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose 
malabsorption. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
There have been no formal interaction studies for AVAGLIM. However, the concomitant use of the 
active substances in patients in clinical studies and in widespread clinical use has not resulted in any 
unexpected interactions. The following statements reflect the information available on the individual 
active substances (rosiglitazone and glimepiride). 
 



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Rosiglitazone 
In vitro studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with 
CYP2C9 as only a minor pathway.  
 
Clinically significant interactions with CYP2C9 substrates or inhibitors are not anticipated. 
 
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). 
 
Concomitant administration of rosiglitazone with the oral anti-diabetic agents metformin, glimepiride, 
glibenclamide and acarbose did not result in any clinically relevant pharmacokinetic interactions.  
 
No clinically relevant interactions with digoxin, the CYP2C9 substrate warfarin, the CYP3A4 
substrates nifedipine, ethinylestradiol or norethindrone were observed after co-administration with 
rosiglitazone. 
 
Glimepiride 
If glimepiride is taken simultaneously with certain other medicines, both undesired increases and 
decreases in the hypoglycaemic action of glimepiride can occur. For this reason, other medicines 
should only be taken with the knowledge (or at the prescription) of the doctor. 
 
Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). Its metabolism is known to be 
influenced by concomitant administration of CYP2C9 inducers (e.g. rifampicin) or inhibitors (e.g. 
fluconazole 
 
Results from an vivo interaction study reported in literature show that glimepiride AUC is increased 
approximately 2-fold by fluconazole, one of the most potent CYP2C9 inhibitors. 
 
Based on the experience with glimepiride and with other sulphonylureas the following interactions 
have to be mentioned. 
 
Potentiation of the blood-glucose-lowering effect and, thus, in some instances hypoglycaemia may 
occur when one of the following drugs is taken, for example: 
 
phenylbutazone, azapropazon and oxyfenbutazone, sulphinpyrazone, 
insulin and oral antidiabetic products,   certain long acting sulphonamides, 
metformin,     tetracyclines, 
salicylates and p-amino-salicylic acid,   MAO-inhibitors, 
anabolic steroids and male sex hormones,  quinolone antibiotics, 
chloramphenicol,     probenecid, 
coumarin anticoagulants,    miconazol, 
fenfluramine,     pentoxifylline (high dose parenteral), 
fibrates,      tritoqualine, 
ACE inhibitors,     fluconazole. 
fluoxetine,  
allopurinol, 
sympatholytics, 
cyclo-, tro-and iphosphamides, 
 



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Weakening of the blood-glucose-lowering effect and, thus raised blood glucose levels may occur when 
one of the following drugs is taken, for example: 
 
oestrogens and progestagens,  
saluretics, thiazide diuretics, 
thyroid stimulating agents, glucocorticoids, 
phenothiazine derivatives, chlorpromazine, 
adrenaline and sympathicomimetics,  
nicotinic acid (high dosages) and nicotinic acid derivatives, 
laxatives (long term use), 
phenytoin, diazoxide, 
glucagon, barbiturates and rifampicin, 
acetozolamide. 
 
H2 antagonists, betablockers, clonidine and reserpine may lead to either potentiation or weakening of 
the blood glucose lowering effect.  
 
Under the influence of sympatholytic drugs such as betablockers, clonidine, guanethidine and 
reserpine, the signs of adrenergic counterregulation to hypoglycaemia may be reduced or absent. 
 
Alcohol intake may potentiate or weaken the hypoglycaemic action of glimepiride in an unpredictable 
fashion.  
 
Glimepiride may either potentiate or weaken the effects of coumarin derivatives. 
 
4.6 Pregnancy and lactation 
 
For AVAGLIM no preclinical or clinical data on exposed pregnancies or lactation are available. 
 
Rosiglitazone has been reported to cross the human placenta and to be detectable in foetal tissues. 
There are no adequate data from the use of either active substance (rosiglitazone and glimepiride) in 
pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential 
risk for humans is unknown.  
 
Therefore, AVAGLIM should not be used during pregnancy and the use of insulin is recommended. If 
a patient wishes to become pregnant or if pregnancy occurs, treatment with AVAGLIM should be 
discontinued. 
 
Both rosiglitazone and glimepiride have been detected in the milk of experimental animals. It is not 
known whether breast-feeding will lead to exposure of the infant to medicinal product. Therefore, 
AVAGLIM should not be used during lactation.  
 
4.7 Effects on ability to drive and use machines 
 
No studies of the effects on the ability to drive and use machines have been performed. Nevertheless, 
the potential for hypoglycaemia should be borne in mind when considering the patient's ability to 
perform tasks that require judgement, motor or cognitive skills (e.g. driving).  
 
4.8 Undesirable effects 
 
Adverse reactions are presented below for each of the component parts of AVAGLIM. An adverse 
reaction is only presented for the fixed dose combination if it has not been seen in one of the 
component parts of AVAGLIM or if it occurred at a higher frequency than that listed for a component 
part. 
 
 
 



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AVAGLIM 
Data from double-blind studies confirm that the safety profile of concomitant rosiglitazone and 
glimepiride is similar to that of the combined adverse reaction profile for the two active substances. 
Limited data with AVAGLIM is also consistent with this combined adverse reaction profile. 
 
Rosiglitazone 
 
Clinical trial data 
Adverse reactions for each treatment regimen are presented below by system organ class and absolute 
frequency. For dose-related adverse reactions the frequency category reflects the higher dose of 
rosiglitazone. Frequency categories do not account for other factors including varying study duration, 
pre-existing conditions and baseline patient characteristics. 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 with rosiglitazone 
 
Adverse reaction Frequency of adverse reaction by treatment regimen 
 Rosiglitazone monotherapy Rosiglitazone with 

sulphonylurea 
 
Blood and the lymphatic system disorders 
anaemia Common Common 
leucopaenia  Common 
thrombocytopaenia  Common 
 
Metabolism and nutrition disorders 
hypercholesterolaemia1 Common Common 
hypertriglyceridaemia Common Common 
hyperlipaemia Common Common 
weight increase Common Common 
increased appetite Common Uncommon 
hypoglycaemia  Very common 
 
Nervous system disorders 
dizziness*  Common 
 
Cardiac disorders 
cardiac failure2  Common 
cardiac ischaemia3* Common Common 
 
Gastrointestinal disorders 
constipation Common Common 
 
Musculoskeletal and connective tissue disorders 
bone fractures4 Common Common 
 
General disorders and administration site conditions 
oedema Common Very common 
 



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*The frequency category for the background incidence of this event, 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 or dual 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 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 
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. 
 
 



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Table 2. The frequency of adverse reactions identified from post-marketing data with 
rosiglitazone 
 
Adverse reaction Frequency 
 
Metabolism and nutrition disorders 
rapid and excessive weight gain Very rare 
 
Immune system disorders (see Skin and subcutaneous tissue disorders) 
anaphylactic reaction Very rare 
 
Eye disorders 
macular oedema Rare 
 
Cardiac disorders 
congestive heart failure/pulmonary oedema Rare 
 
Hepatobiliary disorders 
hepatic dysfunction, primarily evidenced by elevated hepatic enzymes5 Rare 
 
Skin and subcutaneous tissue disorders (see Immune system disorders) 
angioedema Very rare 
skin reactions (e.g. urticaria, pruritis, rash) Very rare 

 
5 Rare cases of elevated liver enzymes and hepatocellular dysfunction have been reported. marketing 
experience. In very rare cases a fatal outcome has been reported. 
 
Glimepiride 
 
Clinical trial data and post-marketing data 
Table 3 presents adverse reactions by system organ class and by frequency category based on 
experience with glimepiride and other sulphonylureas. Frequencies are defined as: very common 
(≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥1/10,000, <1/1000) and 
very rare (<1/10,000 including isolated reports). 
 
Table 3. The frequency of glimepiride adverse reactions identified from clinical trial and post-
marketing data  
 
Adverse reaction Frequency 
 
Blood and lymphatic system disorders 
agranulocytosis Rare 
granulocytopenia Rare 
pancytopenia Rare 
haemolytic anaemia Rare 
thrombocytopenia Rare 
leukopenia Rare 
erythrocytopenia Rare 
 
Immune system disorders6 
allergic vasculitis Very rare 
hypersensitivity reactions7 Very rare 
 
Metabolism and nutrition disorders 
hypoglycaemia8 Very common 



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Gastrointestinal disorders 
vomiting Very rare 
diarrhoea Very rare 
nausea Very rare 
abdominal distension Very rare 
abdominal pain Very rare 
abdominal discomfort Very rare 
 
Hepatobiliary disorders9 
hepatitis10 Very rare 
impairment of liver function (e.g. with cholestasis and jaundice) Very rare 
 
Skin and subcutaneous tissue disorders11 
hypersensitivity of the skin to light  Very rare 
 
Investigations 
serum sodium decrease Very rare 
 
6 Cross-allergenicity with sulphonylureas, sulphonamides or related substances is possible. 
7 Mild hypersensitivity reactions  may develop into serious reactions with dyspnoea, fall in blood 
pressure and sometimes shock. 
 
8 Based on what is known of other sulphonylureas, hypoglycaemia may be prolonged. Rarely 
hypoglycaemic reactions can occur immediately and may be severe and not always easy to correct. 
 
9 Elevation of liver enzymes may occur. 
10 Hepatitis  may progress to liver failure. 
 
11 Hypersensitivity reactions of the skin may occuras itching, rash and urticaria. 
 
Transient visual disturbances may occur especially on initiation of treatment, due to changes in blood 
glucose levels. 
 
4.9 Overdose 
 
No data are available with regard to overdose of AVAGLIM. 
 
Limited data are available with regard to overdose of rosiglitazone in humans. In clinical studies in 
volunteers rosiglitazone has been administered at single oral doses of up to 20 mg and was well 
tolerated. 
 
Overdose of sulphonylureas, including glimepiride, can result in severe life-threatening 
hypoglycaemia lasting 12 to 72 hours, which may recur after apparent recovery. The symptoms may 
be delayed for up to 24 hours after ingestion. Hospitalisation should be considered as appropriate. 
 
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 and glimepiride are both highly 
protein bound and would not be expected to be cleared by haemodialysis. 
 
 
 
 
 
 
 



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5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Combinations of oral blood glucose lowering drugs, ATC code: 
A10BD04 
 
AVAGLIM combines two antidiabetic agents with complimentary mechanisms of action to improve 
glycaemic control in patients with type 2 diabetes: rosiglitazone maleate, a member of the 
thiazolidinedione class and glimepiride, a member of the sulphonylurea class. Thiazolidinediones act 
primarily by reducing insulin resistance and sulphonylureas act primarily by stimulating release of 
insulin from functioning pancreatic β-cells. A study comparing AVAGLIM to monotherapy 
rosiglitazone or glimepiride demonstrated incremental benefit in control of glycaemia of the 
fixed-dose combination over monotherapy.  No new safety findings were observed. The clinical trial 
program in support of this fixed dose combination only compared rosiglitazone and glimepiride to 
glimepiride monotherapy and not to monotherapy with other sulphonylureas. 
 
Rosiglitazone 
Rosiglitazone is a selective agonist at the PPARγ (peroxisome proliferator activated receptor gamma) 
nuclear receptor and is a member of the thiazolidinedione class of antihyperglycaemic agents. It 
reduces glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver. 
 
The antihyperglycaemic activity of rosiglitazone has been demonstrated in a number of animal models 
of type 2 diabetes. In addition, rosiglitazone preserved ß-cell function as shown by increased 
pancreatic islet mass and insulin content and prevented the development of overt hyperglycaemia in 
animal models of type 2 diabetes. Rosiglitazone did not stimulate pancreatic insulin secretion or 
induce hypoglycaemia in rats and mice. The major metabolite (a para-hydroxy-sulphate) with high 
affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in 
obese mice. The clinical relevance of this observation has not been fully elucidated. 
 
In clinical trials, the glucose lowering effects observed with rosiglitazone are gradual in onset with 
near maximal reductions in fasting plasma glucose (FPG) evident following approximately 8 weeks of 
therapy. The improved glycaemic control is associated with reductions in both fasting and post-
prandial glucose. 
 
Rosiglitazone was associated with increases in weight. In mechanistic studies, the weight increase was 
predominantly shown to be due to increased subcutaneous fat with decreased visceral and intra-hepatic 
fat. 
 
Consistent with the mechanism of action, rosiglitazone 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. 
 
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, 



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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). 
 
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. 
 
Glimepiride 
Glimepiride is an orally active hypoglycaemic substance belonging to the sulphonylurea group. It may 
be used in non-insulin dependent diabetes mellitus. 
Glimepiride acts mainly by stimulating the release of insulin from the beta cells of the pancreas. As 
with other sulphonylureas, this effect is based on an improvement in responsiveness of pancreatic beta 
cells to the physiological glucose stimulus. In addition, glimepiride seems to have pronounced 
extrapancreatic effects, also postulated for other sulphonylureas. 
 



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Sulphonylureas regulate insulin secretion by closing the ATP-dependent potassium channels in the 
beta cell membrane. Closure of the potassium channels leads to depolarisation of the beta cell and 
results by opening of the calcium channels – to an increased influx of calcium into the cell. This leads 
to a release of insulin by exocytosis. 
 
Glimepiride binds with a high exchange rate to a beta cell membrane protein which is associated with 
the ATP-sensitive potassium channel but which differs from the usual sulphonylurea binding site. 
 
Extrapancreatic effects include an improvement in insulin sensitivity of peripheral tissue and a 
reduction in hepatic uptake of insulin. 
Glimepiride very rapidly increases the number of active glucose transport molecules in the plasma 
membranes of muscle and fat cells, resulting in stimulation of glucose uptake. 
Glimepiride increases the activity of glycosyl-phosphatidylinositol-specific phospholipase C, which 
may be associated with drug-induced lipogenesis and glycogenesis in isolated fat and muscle cells. 
Glimepiride inhibits the hepatic glucose production by increasing the intracellular concentration of 
fructose-2,6 bisphosphate, which in turn inhibits gluconeogenesis. 
 
The minimum effective oral dose is approximately 0.6 mg. The effect of glimepiride is dose-
dependent and reproducible. The physiological response to acute physical exercise, a reduction in 
insulin secretion, is maintained during treatment with glimepiride. 
There was no significant difference in the effect regardless of whether the drug was taken 30 minutes 
before or immediately before a meal. In diabetic patients, good metabolic control over 24 hours can be 
achieved with a single daily dose. 
Although the hydroxy metabolite of glimepiride caused a small but significant reduction in serum 
glucose, it accounts for only a minor part of the total drug effect. 
 
5.2 Pharmacokinetic properties 
 
AVAGLIM 
 
Single oral doses of glimepiride in 14 healthy adult subjects had no clinically significant effect on the 
steady-state pharmacokinetics of rosiglitazone. No clinically significant reductions in glimepiride 
AUC and Cmax were observed after repeat doses of rosiglitazone for eight days in healthy adult 
subjects.  
 
In a bioequivalence study under fasted conditions, the AUC and Cmax of rosiglitazone and the AUC of 
glimepiride following a single dose of a 4 mg/4 mg combination tablet were bioequivalent to 
concomitant administration of rosiglitazone 4 mg and glimepiride 4 mg. 
 
In the fed state, the rate and extent of absorption of the rosiglitazone-glimepiride 4 mg/4 mg 
combination were equivalent to concomitant administration of 4 mg rosiglitazone and 4 mg 
glimepiride. Administration of the 4 mg/4 mg combination with food led to an increase in glimepiride 
exposure compared to that observed on administration in the fasted state. Glimepiride AUC0-t, AUC0-inf 
and Cmax were increased by 30%, 19% and 55% respectively, on average. For rosiglitazone, Cmax 
values were decreased by approximately 32% with food. 
 
The AUC and Cmax of glimepiride increased in a dose-proportional manner following administration of 
rosiglitazone-glimepiride 4 mg/1 mg, 4 mg/2 mg, and 4 mg/4 mg.  
 
The following statements reflect the pharmacokinetic properties of the individual components of 
AVAGLIM. 
 
Rosiglitazone 
Absorption 
Absolute bioavailability of rosiglitazone following both a 4 and an 8 mg oral dose is approximately 
99%. Rosiglitazone plasma concentrations peak at around 1 h after dosing. Plasma concentrations are 
approximately dose proportional over the therapeutic dose range. 



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Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), although a 
small decrease in Cmax (approximately 20-28%) and a delay in tmax (approximately 1.75 h) were 
observed compared to dosing in the fasted state. These small changes are not clinically significant and, 
therefore, it is not necessary to administer rosiglitazone at any particular time in relation to meals. The 
absorption of rosiglitazone is not affected by increases in gastric pH. 
 
Distribution 
The volume of distribution of rosiglitazone is approximately 14 l in healthy volunteers. Plasma protein 
binding of rosiglitazone is high (approximately 99.8%) and is not influenced by concentration or age. 
The protein binding of the major metabolite (a para-hydroxy-sulphate) is very high (> 99.99%). 
 
Metabolism 
Metabolism of rosiglitazone is extensive with no parent compound being excreted unchanged. The 
major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with 
sulphate and glucuronic acid. The contribution of the major metabolite (a para-hydroxy-sulphate) to 
the overall antihyperglycaemic activity of rosiglitazone has not been fully elucidated in man and it 
cannot be ruled out that the metabolite may contribute to the activity. However, this raises no safety 
concern regarding target or special populations as hepatic impairment is contraindicated and the phase 
III clinical studies included a considerable number of elderly patients and patients with mild to 
moderate renal impairment. 
 
In vitro studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor 
contribution by CYP2C9. 
Since there is no significant in vitro inhibition of CYP1A2, 2A6, 2C19, 2D6, 2E1, 3A or 4A with 
rosiglitazone, there is a low probability of significant metabolism-based interactions with substances 
metabolised by these P450 enzymes. Rosiglitazone showed moderate inhibition of CYP2C8 
(IC50 18 µM) and low inhibition of CYP2C9 (IC50 50 µM) in vitro (see section 4.5). An in vivo 
interaction study with warfarin indicated that rosiglitazone does not interact with CYP2C9 substrates 
in vivo. 
 
Elimination 
Total plasma clearance of rosiglitazone is around 3 l/h and the terminal elimination half-life of 
rosiglitazone is approximately 3-4 h. There is no evidence for unexpected accumulation of 
rosiglitazone after once or twice daily dosing. The major route of excretion is the urine with 
approximately two-thirds of the dose being eliminated by this route, whereas faecal elimination 
accounts for approximately 25% of dose. No intact active substance is excreted in urine or faeces. The 
terminal half-life for radioactivity was about 130 h indicating that elimination of metabolites is very 
slow. Accumulation of the metabolites in plasma is expected upon repeated dosing, especially that of 
the major metabolite (a para-hydroxy-sulphate) for which an 8-fold accumulation is anticipated. 
 
Glimepiride 
Absorption 
After oral administration, glimepiride is completely (100%) absorbed from the gastrointestinal tract. 
Studies with single oral doses in normal subjects and with multiple oral doses in patients with type 2 
diabetes mellitus have shown significant absorption of glimepiride within 1 h after administration and 
Cmax at approximately 2.5 h. There is a linear relationship between dose and both Cmax and AUC. 
 
Distribution 
After intravenous dosing in normal subjects, the volume of distribution was 8.8 l (113 ml/kg), and the 
total body clearance was 47.8 ml/min. Protein binding was greater than 99.5%. 
 
Metabolism 
Glimepiride is completely metabolised by oxidative biotransformation after either an intravenous or 
oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl 
derivative (M2). CYP2C9 has been shown to be involved in the biotransformation of glimepiride to 
M1. M1 is further metabolised to M2 by one or several cytosolic enzymes. M1, but not M2, possesses 



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about 1/3 of the pharmacological activity as compared to its parent in an animal model. The clinical 
significance of the glucose-lowering effect of M1 is unclear. 
 
Elimination 
The elimination half-life of glimepiride is approximately 5 to 8 h. When 14C-glimepiride was given 
orally, approximately 60% of the total radioactivity was recovered in the urine in seven days and M1 
(predominant) and M2 accounted for 80 to 90% of that recovered in the urine. Approximately 40% of 
the total radioactivity was recovered in faeces and M1 and M2 (predominant) accounted for about 70% 
of that recovered in faeces. No parent drug was recovered from urine or faeces. After intravenous 
dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite was observed. 
 
 
Special populations 
Gender: In the pooled population pharmacokinetic analysis, there were no marked differences in the 
pharmacokinetics of rosiglitazone or glimepiride between males and females. 
 
Elderly: In the pooled population pharmacokinetic analysis, age was not found to influence the 
pharmacokinetics of rosiglitazone or glimepiride to any significant extent. 
 
Hepatic impairment: Following rosiglitazone treatment 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. No adequate pharmacokinetic studies of glimepiride have been conducted in subjects with 
functional hepatic impairment. Therefore AVAGLIM should not be used in patients with hepatic 
impairment (see section 4.3) 
 
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. There 
are no data from the use of glimepiride in patients on renal dialysis (see section 4.3). 
 
A multiple-dose titration study with glimepiride conducted in 16 patients with type 2 diabetes mellitus 
with renal impairment using doses ranging from 1 to 8 mg daily for three months showed that all 
patients with a creatinine clearance less than 22 ml/min had adequate control of their glucose levels 
with a dosage regimen of only 1 mg daily (see section 4.2 and 4.4). 
 
5.3 Preclinical safety data 
 
No animal studies have been conducted with the combined products in AVAGLIM. The following 
data are findings in studies performed with rosiglitazone or glimepiride individually. 
 
Rosiglitazone 
Undesirable effects observed in animal studies with possible relevance to clinical use were as follows: 
An increase in plasma volume accompanied by decrease in red cell parameters and increase in heart 
weight. Increases in liver weight, plasma ALT (dog only) and fat tissue were also observed.  Similar 
effects have been seen with other thiazolidinediones. 
 
In reproductive toxicity studies, administration of rosiglitazone to rats during mid-late gestation was 
associated with foetal death and retarded foetal development. In addition, rosiglitazone inhibited 
ovarian oestradiol and progesterone synthesis and lowered plasma levels of these hormones resulting 
in effects on oestrus/menstrual cycles and fertility (see section 4.4). 
 
In an animal model for familial adenomatous polyposis (FAP), treatment with rosiglitazone at 200 
times the pharmacologically active dose increased tumour multiplicity in the colon. The relevance of 
this finding is unknown. However, rosiglitazone promoted differentiation and reversal of mutagenic 
changes in human colon cancer cells in vitro. In addition, rosiglitazone was not genotoxic in a battery 
of in vivo and in vitro genotoxicity studies and there was no evidence of colon tumours in lifetime 
studies of rosiglitazone in two rodent species. 



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Glimepiride 
 Preclinical effects were observed only at exposures considered sufficiently in excess of the maximum 
human exposure indicating little relevance to clinical use or were caused by the pharmacodynamic 
effect (hypoglycaemia) of the substance. This was based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and fertility. Studies on 
embryofoetal development and pre-and postnatal development revealed eye malformations, skeletal 
anomalies, abortions, and an increased foetal death rate. 
Reproduction toxicology findings may be related to the pharmacodynamic action of glimepiride. 
Glimepiride is excreted into the milk of lactating rats. High doses given to mother rats cause 
hypoglycaemia in suckling young rats (see section 4.6). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
8/4 
Tablet core:  
Sodium starch glycolate Type A 
Hypromellose (E464) 
Microcrystalline cellulose (E460) 
Lactose monohydrate 
Magnesium stearate. 
 
Film coat: 
Hypromellose (E464) 
Titanium dioxide (E171) 
Macrogol 400 
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 blisters (PVC/PVDC/aluminium). Packs of 14, 28, 56, 84 or 112 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/1/06/349/005-008 
EU/1/06/349/010 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
27 June 2006 
 
 
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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ANNEX II 
 

A. MANUFACTURING AUTHORISATION HOLDER 
RESPONSIBLE FOR BATCH RELEASE 

 
B. CONDITIONS OF THE MARKETING AUTHORISATION 

 



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A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH 
RELEASE 

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

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

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Not aplicable. 
 
• 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 
− At the request of the EMEA. 



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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



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A. LABELLING 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVAGLIM 4 mg/4 mg film-coated tablets. 
rosiglitazone/glimepiride 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains rosiglitazone maleate corresponding to 4 mg rosiglitazone and 4 mg glimepiride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
film-coated tablets 
 
14 tablets 
28 tablets 
56 tablets 
84 tablets 
112 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Use only as directed by your doctor 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/349/001  14 tablets 
EU/1/06/349/002  28 tablets 
EU/1/06/349/003  56 tablets 
EU/1/06/349/004  112 tablets 
EU/1/06/349/009  84 tablets 
 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
AVAGLIM 4 mg/4 mg 



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVAGLIM 4 mg/4 mg film-coated tablets. 
rosiglitazone/glimepiride 
 
 
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 
 
AVAGLIM 8 mg/4 mg film-coated tablets. 
rosiglitazone/glimepiride 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains rosiglitazone maleate corresponding to 8 mg rosiglitazone and 4 mg glimepiride. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
film-coated tablets 
 
14 tablets 
28 tablets 
56 tablets 
84 tablets 
112 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Use only as directed by your doctor 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd 
980 Great West Road 
Brentford, Middlesex TW8 9GS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/349/005  14 tablets 
EU/1/06/349/006  28 tablets 
EU/1/06/349/007  56 tablets 
EU/1/06/349/008  112 tablets 
EU/1/06/349/010  84 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
AVAGLIM 8 mg/4 mg 



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
AVAGLIM 8 mg/4 mg film-coated tablets. 
rosiglitazone/glimepiride 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SmithKline Beecham Ltd  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 



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B. PACKAGE LEAFLET 



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PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

AVAGLIM 4 mg/4 mg film-coated tablets 
AVAGLIM 8 mg/4 mg film-coated tablets 

rosiglitazone/glimepiride 
 
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 Avaglim is and what it is used for 
2. Before you take Avaglim 
3. How to take Avaglim 
4. Possible side effects 
5 How to store Avaglim 
6. Further information 
 
 
1. WHAT AVAGLIM IS AND WHAT IT IS USED FOR 
 
Avaglim tablets are a combination of two different medicines called rosiglitazone and glimepiride. 
These two medicines are used to treat type 2 diabetes. 
 
People with type 2 diabetes either don’t make enough insulin (a hormone that controls blood sugar 
levels), or don’t respond normally to the insulin their body makes. Rosiglitazone and glimepiride work 
together so your body makes better use of the insulin it produces, and this helps reduce your blood 
sugar to a normal level. 
 
 
2. BEFORE YOU TAKE AVAGLIM 
 
To help manage your diabetes, it is important that you follow any diet and lifestyle advice from your 
doctor as well as taking Avaglim. 
 
Don’t take Avaglim: 

• if you are allergic (hypersensitive) to rosiglitazone, glimepiride, or any of the other 
ingredients of Avaglim (listed in Section 6), or to other medicines called sulphonylureas 
(like glibenclamide) or sulphonamides 

• 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) 
• if you have severe kidney disease  
• if you have type 1 diabetes – this needs different treatment. 

     Check with your doctor if you think any of these apply to you. Don’t take Avaglim. 
 
Take special care with Avaglim 
 
Avaglim is not recommended for people aged under 18, as the safety and effectiveness are not 
known.  



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

     Check with your doctor, as Avaglim may not be suitable for you. 
 
Haemolytic anaemia: If you have an inherited condition where your red blood cells don’t produce 
enough of the enzyme G6PD, Avaglim may cause your red blood cells to be destroyed too quickly 
(haemolytic anaemia). 

 Tell your doctor if you have this condition, as Avaglim may not be suitable for you. 
 
Conditions to look out for 
Avaglim 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 Avaglim, 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 Avaglim. 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). 
 
You will have regular blood tests 
Avaglim can cause reductions in some types of blood cells. Your doctor should regularly test your 
blood while you are taking Avaglim. 
 
Your kidney function will be checked 
If you have kidney disease, or are over 65, your kidney function should be checked while you are 
taking Avaglim. 
 
 
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. 
 
Many medicines (or alcohol) can affect the way Avaglim controls the amount of sugar in your blood. 
Your blood sugar levels may become too high or too low (see ‘Low blood sugar’ in Section 4). Some 
of the medicines most likely to do this are: 
• gemfibrozil (used to lower cholesterol) 
• rifampicin (used to treat tuberculosis and other infections) 
• fluconazole (used to treat fungal infections). 

 Tell a doctor or pharmacist if you think that Avaglim is not working as it should, particularly if 
you are taking any other medicines. You may need to have the dose adjusted or change the other 
medicines you are taking. 

 
Some medicines used to treat high blood pressure (such as beta-blockers, clonidine, guanethidine or 
reserpine) may make you less aware of the warning signs of low blood sugar (sweating; fast irregular 
heartbeats). 

 Checking your blood sugar levels regularly is especially important if you are taking any of these 
medicines, even if you are feeling well 

 
Avaglim can also strengthen or weaken the effects of medicines to prevent blood clots 
(anticoagulants such as warfarin). 

 Tell your doctor or pharmacist if you are taking anticoagulants. 
 
 



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

your doctor. 
 
• Don’t breast-feed while you are taking Avaglim. The ingredients may pass into breast milk and 

so may harm your baby. 
 
Driving and using machines 
Avaglim can make you dizzy or cause your blood sugar to become lower than normal (see ‘Low blood 
sugar’ in Section 4). 

 Don’t drive or operate machinery unless you’re feeling well. 
 
Avaglim contains lactose  
Avaglim 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 AVAGLIM 
 
Always take Avaglim tablets exactly as your doctor has told you. Do not take more than the 
recommended dose. Check with your doctor or pharmacist if you are not sure. 
 
How much to take 
The usual starting dose is one combined tablet (4 mg rosiglitazone and 4 mg glimepiride), taken once 
a day. 
 
After about 8 weeks your doctor may need to increase your dose. The maximum dose is one combined 
tablet of 8 mg rosiglitazone and 4 mg glimepiride, taken once a day. 
 
How to take 
Swallow the tablets with some water. 
 
It is best to take Avaglim with food, or just before food, usually with your first main meal of the day. 
 
Take your tablets around the same time every day and follow any dietary advice that your doctor has 
given you. 
 
If you take more Avaglim than you should  
If you accidentally take too many tablets, contact your doctor or pharmacist for advice. You may be at 
risk of having low blood sugar and need hospital treatment. 
 
If you forget to take Avaglim 
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 Avaglim 
Take Avaglim for as long as your doctor recommends. If you stop taking Avaglim, your blood sugar 
will not be controlled, and you may become unwell. Talk to your doctor if you want to stop. 
 
 



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4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Avaglim 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 Avaglim. 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 Avaglim. 
 
Fluid retention and heart failure: Avaglim 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): Certain conditions can make you more likely to suffer from low 
blood sugar while you are taking Avaglim. These include: 
 taking other medicines to treat diabetes 
 kidney disease 
 low body weight or poor diet 
 stress situations (such as trauma, surgery or infections) 

 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 Avaglim 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 Avaglim and similar medicines.   

 Discuss with your doctor any concerns about your eyesight.   
 
Broken bones: Bone fractures can occur in people with diabetes. The chances of this happening may 
be higher in people, particularly women, taking rosiglitazone for more than one year. The most 
common are breaks in feet, hands and arms. 
 
 



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Very common side effects 
These may affect more than 1 in 10 people: 

• lower blood sugar than normal (hypoglycaemia) 
• swelling (oedema) due to water retention. 

 
Common side effects 
These may affect up to 1 in 10 people: 

• chest pain (angina) 
• heart failure 
• broken bones 
• increased weight, increased appetite 
• dizziness 
• constipation 
• reduction in blood count (anaemia) low numbers of white blood cells (leucopaenia) and blood 

cells needed for blood clotting (thrombocytopaenia) 
• small increases in blood cholesterol, increased amount of fats in the blood 

 
Rare side effects  
These may affect up to 1 in 1,000 people: 

• fluid in the lungs (pulmonary oedema) causing breathlessness 
• swelling of the retina at the back of the eye (macular oedema) 
• reduction in the number of red blood cells, or a type of white blood cell (granulocytopaenia) 

which can be severe (agranulocytosis), reduction in the number of all types of blood cells 
(pancytopaenia) 

• liver doesn’t function as well as it should (increase in liver enzymes). 
 
Very rare side effects  
These may affect up to 1 in 10,000 people: 

• allergic reactions, inflammation of blood vessels (allergic vasculitis) 
• increased sensitivity to the sun causing skin rash 
• inflammation of the liver (hepatitis), yellowing of the skin (jaundice) 
• rapid and excessive weight gain caused by fluid retention 
• stomach pain, bloating, feeling sick (nausea), vomiting or diarrhoea 
• decrease in the amount of sodium in your blood. 

If you get side effects 
 Tell your doctor or pharmacist if any of the side effects listed gets severe or troublesome, or if 

you notice any side effects not listed in this leaflet. 
 
 
5. HOW TO STORE AVAGLIM 
 
Keep out of the reach and sight of children.  
 
Do not use Avaglim 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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6. FURTHER INFORMATION 
 
What Avaglim contains 
The active substances are rosiglitazone and glimepiride. Avaglim tablets come in different strengths.  
Each tablet contains either: 4 mg or 8 mg rosiglitazone and 4 mg glimepiride. 
 
The other ingredients are: sodium starch glycollate (Type A), hypromellose (E464), microcrystalline 
cellulose (E460), lactose monohydrate, magnesium stearate, titanium dioxide (E171), macrogol 400, 
iron oxide black and/or red (E172). 
 
What Avaglim looks like and contents of the pack 
Avaglim 4 mg/4 mg tablets are pink, rounded triangular-shaped, and marked "gsk" on one side and 
"4/4" on the other. 
 
Avaglim 8 mg/4 mg tablets are red, rounded triangular-shaped, and marked "gsk" on one side and 
"8/4" on the other. 
 
The tablets are supplied in blister packs containing 14, 28, 56, 84 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 S.A., Avenida de Extremadura 3, 09400 Aranda de Duero, Burgos, 
Spain. 



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For any information about this medicine, 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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Italia 
GlaxoSmithKline S.p.A. 
Tel: + 39 (0)45 9218 111 

Suomi/Finland 
GlaxoSmithKline Oy 
Puh/Tel: + 358 (0)10 30 30 30 
Finland.tuoteinfo@gsk.com 
 

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

Sverige 
GlaxoSmithKline AB 
Tel: + 46 (0)8 638 93 00 
info.produkt@gsk.com 
 

Latvija 
GlaxoSmithKline Latvia SIA 
Tel: + 371 67312687 
lv-epasts@gsk.com 

United Kingdom 
GlaxoSmithKline UK 
Tel: + 44 (0)800 221441 
customercontactuk@gsk.com 
 

Lietuva 
GlaxoSmithKline Lietuva UAB 
Tel: + 370 5 264 90 00 
info.lt@gsk.com 
 

 

 
This leaflet was last approved in  
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: 
http://www.ema.europa.eu/ 
<------------------------------------------------------------------------------------------------------------------------------ 
 


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