Avandamet 2 mg/500 mg film-coated tablets .

Avandamet 2 mg/1000 mg film-coated tablets .

Avandamet 4 mg/1000 mg film-coated tablets .

Each tablet contains rosiglitazone maleate corresponding to 2 or 4mg rosiglitazone in combination with metformin hydrochloride 500 mg or 1000 mg (corresponding to metformin free base 390 mg or 780 mg respectively).

Excipient

AVANDAMET 2 mg/500 mg and AVANDAMET 2 mg/1000 mg – Each tablet contains lactose (approximately 11 mg)

AVANDAMET 4 mg/1000 mg - Contains lactose (approximately 23 mg)

For a full list of excipients, see section 6.1.

Film-coated tablet.

AVANDAMET 2 mg/500 mg - Pale pink film-coated tablets marked "gsk" on one side and "2/500" on the other.

AVANDAMET 2 mg/1000 mg - Yellow film-coated tablets marked "gsk" on one side and "2/1000" on the other.

AVANDAMET 4 mg/1000 mg - Pink film-coated tablets marked "gsk" on one side and "4/1000" on the other.

AVANDAMET is indicated in the treatment of type 2 diabetes mellitus patients, particularly overweight patients:

- who are unable to achieve sufficient glycaemic control at their maximally tolerated dose of oral metformin alone.

- in triple oral therapy with sulphonylurea in patients with insufficient glycaemic control despite dual oral therapy with their maximally tolerated dose of metformin and a sulphonylurea (see section 4.4).

For the different dosage regimens, AVANDAMET is available in appropriate strengths.

The usual starting dose of AVANDAMET is 4 mg/day rosiglitazone plus 2000 mg/day metformin hydrochloride.

Rosiglitazone can be increased to 8 mg/day after 8 weeks if greater glycaemic control is required. The maximum recommended daily dose of AVANDAMET is 8 mg rosiglitazone plus 2000 mg metformin hydrochloride.

The total daily dose of AVANDAMET should be given in two divided doses.

Dose titration with rosiglitazone (added to the optimal dose of metformin) may be considered before the patient is switched to AVANDAMET.

When clinically appropriate, direct change from metformin monotherapy to AVANDAMET may be considered.

Taking AVANDAMET with or just after food may reduce gastrointestinal symptoms associated with metformin.

Triple oral therapy (rosiglitazone, metformin and sulphonylurea) (see section 4.4)

- Patients on metformin and sulphonylurea: when appropriate AVANDAMET may be initiated at 4 mg/day rosiglitazone with the dose of metformin substituting that already being taken. An increase in the rosiglitazone component to 8 mg/day should be undertaken cautiously following appropriate clinical evaluation to assess the patient's risk of developing adverse reactions relating to fluid retention (see sections 4.4 and 4.8).

- Patients established on triple oral therapy: when appropriate, AVANDAMET may substitute rosiglitazone and metformin doses already being taken.

Where appropriate, AVANDAMET may be used to substitute concomitant rosiglitazone and metformin in existing dual or triple oral therapy to simplify treatment.

Elderly

As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal function, elderly patients taking AVANDAMET should have their renal function monitored regularly (see sections 4.3 and 4.4).

Patients with renal impairment

AVANDAMET should not be used in patients with renal failure or renal dysfunction e.g. serum creatinine levels> 135 μmol/l in males and> 110 μmol/l in females and/or creatinine clearance < 70 ml/min (see sections 4.3 and 4.4).

Children and adolescents

AVANDAMET is not recommended for use in children and adolescents below 18 years of age as there are no data available on its safety and efficacy in this age group (see sections 5.1 and 5.2).

AVANDAMET is contraindicated in patients with:

- hypersensitivity to rosiglitazone, metformin hydrochloride or to any of the excipients

- cardiac failure or history of cardiac failure (New York Heart Association (NYHA) stages I to IV)

- an Acute Coronary Syndrome (unstable angina, NSTEMI and STEMI) (see section 4.4)

- acute or chronic disease which may cause tissue hypoxia such as:

- hepatic impairment

- acute alcohol intoxication, alcoholism (see section 4.4)

- diabetic ketoacidosis or diabetic pre-coma

- renal failure or renal dysfunction e.g. serum creatinine levels> 135 µmol/l in males and> 110 µmol/l in females and/or creatinine clearance < 70 ml/min (see section 4.4)

- acute conditions with the potential to alter renal function such as:

- lactation.

Lactic acidosis

Lactic acidosis is a very rare, but serious, metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with hypoxia.

Diagnosis:

Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment with the medicinal product should be discontinued and the patient hospitalised immediately (see section 4.9).

Renal function

As metformin is excreted by the kidney, serum creatinine concentrations should be determined regularly:

- at least once a year in patients with normal renal function

- at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly patients.

Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive or diuretic therapy or when starting treatment with an NSAID.

Fluid retention and cardiac failure

Thiazolidinediones can cause fluid retention which may exacerbate or precipitate signs or symptoms of congestive heart failure. Rosiglitazone can cause dose-dependent fluid retention. The possible contribution of fluid retention to weight gain should be individually assessed as rapid and excessive weight gain has been reported very rarely as a sign of fluid retention. All patients, particularly those receiving concurrent insulin but also sulphonylurea therapy, those at risk for heart failure, and those with reduced cardiac reserve, should be monitored for signs and symptoms of adverse reactions relating to fluid retention, including weight gain and heart failure. AVANDAMET must be discontinued if any deterioration in cardiac status occurs.

The use of AVANDAMET in combination with a sulphonylurea or insulin may be associated with increased risks of fluid retention and heart failure (see section 4.8). The decision to initiate AVANDAMET in combination with a sulphonylurea should include consideration of alternative therapies. Increased monitoring of the patient is recommended if AVANDAMET is used in combination particularly with insulin but also with a sulphonylurea.

Heart failure was also reported more frequently in patients with a history of heart failure, oedema and heart failure was also reported more frequently in elderly patients and in patients with mild or moderate renal failure. Caution should be exercised in patients over 75 years because of the limited experience in this patient group. Since NSAIDs, insulin and rosiglitazone are all associated with fluid retention, concomitant administration may increase the risk of oedema.

Combination with insulin

An increased incidence of cardiac failure has been observed in clinical trials when rosiglitazone is used in combination with insulin. Insulin and rosiglitazone are both associated with fluid retention, concomitant administration may increase the risk of oedema and could increase the risk of ischaemic heart disease. Insulin should only be added to established rosiglitazone therapy in exceptional cases and under close supervision.

Myocardial Ischaemia

A retrospective analysis of data from 42 pooled short-term clinical studies indicated that treatment with rosiglitazone may be associated with an increased risk of myocardial ischaemic events. However, in their entirety the available data on the risk of cardiac ischaemia are inconclusive (see section 4.8). There are limited clinical trial data in patients with ischaemic heart disease and/or peripheral arterial disease. Therefore, as a precaution, the use of rosiglitazone is not recommended in these patients, particularly those with myocardial ischaemic symptoms.

Acute Coronary Syndrome (ACS)

Patients experiencing an ACS have not been studied in rosiglitazone controlled clinical trials. In view of the potential for development of heart failure in these patients, rosiglitazone should therefore not be initiated in patients having an acute coronary event and it should be discontinued during the acute phase (see section 4.3).

Monitoring of liver function

There have been rare reports of hepatocellular dysfunction during post-marketing experience with rosiglitazone (see section 4.8). There is limited experience with rosiglitazone in patients with elevated liver enzymes (ALT> 2.5 times the upper limit of normal). Therefore, liver enzymes should be checked prior to the initiation of therapy with AVANDAMET in all patients and periodically thereafter based on clinical judgement. Therapy with AVANDAMET should not be initiated in patients with increased baseline liver enzyme levels (ALT> 2.5 times the upper limit of normal) or with any other evidence of liver disease. If ALT levels are increased to> 3 times the upper limit of normal during AVANDAMET therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain> 3 times the upper limit of normal, therapy should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with AVANDAMET should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, therapy should be discontinued.

Eye disorders

Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual acuity have been reported with thiazolidinediones, including rosiglitazone. Many of these patients reported concurrent peripheral oedema. It is unclear whether or not there is a direct association between rosiglitazone and macular oedema but prescribers should be alert to the possibility of macular oedema if patients report disturbances in visual acuity and appropriate ophthalmologic referral should be considered.

Weight gain

In clinical trials with rosiglitazone there was evidence of dose-related weight gain, which was greater when used in combination with insulin. Therefore weight should be closely monitored, given that it may be attributable to fluid retention, which may be associated with cardiac failure.

Anaemia

Rosiglitazone treatment is associated with a dose-related reduction of haemoglobin levels. In patients with low haemoglobin levels before initiating therapy, there is an increased risk of anaemia during treatment with AVANDAMET.

Hypoglycaemia

Patients receiving AVANDAMET in combination with a sulphonylurea or insulin may be at risk for doserelated hypoglycaemia. Increased monitoring of the patient and a reduction in the dose of the concomitant agent may be necessary.

Surgery

As AVANDAMET contains metformin hydrochloride, the treatment should be discontinued 48 hours before elective surgery with general anaesthesia and should not usually be resumed earlier than 48 hours afterwards.

Administration of iodinated contrast agent

The intravascular administration of iodinated contrast agents in radiological studies can lead to renal failure. Therefore, due to the metformin active substance, AVANDAMET should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.5).

Bone disorders

Long-term studies show an increased incidence of bone fractures in patients, particularly female patients, taking rosiglitazone (see section 4.8). The majority of the fractures have occurred in the upper limbs and distal lower limbs. In females, this increased incidence was noted after the first year of treatment and persisted during long-term treatment. The risk of fracture should be considered in the care of patients, especially female patients, treated with rosiglitazone.

Other precautions

Premenopausal women have received rosiglitazone during clinical studies. Although hormonal imbalance has been seen in preclinical studies (see section 5.3), no significant undesirable effects associated with menstrual disorders have been observed. As a consequence of improving insulin sensitivity, resumption of ovulation may occur in patients who are anovulatory due to insulin resistance. Patients should be aware of the risk of pregnancy (see section 4.6).

AVANDAMET should be used with caution during concomitant administration of CYP2C8 inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin), due to the effect on rosiglitazone pharmacokinetics (see section 4.5). Furthermore, AVANDAMET should be used with caution during concomitant administration of cationic medicinal productsthat are eliminated by renal tubular secretion (e.g. cimetidine) due to the effect on metformin pharmacokinetics (see section 4.5). Glycaemic control should be monitored closely. AVANDAMET dose adjustment within the recommended posology or changes in diabetic treatment should be considered.

All patients should continue their diet with regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.

The usual laboratory tests for diabetes monitoring should be performed regularly.

AVANDAMET tablets contain lactose and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

There have been no formal interaction studies for AVANDAMET, however the concomitant use of the active substances in patients in clinical studies and in widespread clinical use has not resulted in any unexpected interactions. The following statements reflect the information available on the individual active substances (rosiglitazone and metformin).

There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of AVANDAMET (see section 4.4). Avoid consumption of alcohol and medicinal products containing alcohol.

Cationic medicinal products that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems. A study conducted in seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased metformin systemic exposure (AUC) by 50% and C_max by 81%. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic medicinal productsthat are eliminated by renal tubular secretion are co-administered (see section 4.4).

In vitro studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with CYP2C9 as only a minor pathway.

Co-administration of rosiglitazone with gemfibrozil (an inhibitor of CYP2C8) resulted in a twofold increase in rosiglitazone plasma concentrations. Since there is a potential for an increase in the risk of dose-related adverse reactions, a decrease in rosiglitazone dose may be needed. Close monitoring of glycaemic control should be considered (see section 4.4).

Co-administration of rosiglitazone with rifampicin (an inducer of CYP2C8) resulted in a 66% decrease in rosiglitazone plasma concentrations. It cannot be excluded that other inducers (e.g. phenytoin, carbamazepine, phenobarbital, St John's wort) may also affect rosiglitazone exposure. The rosiglitazone dose may need to be increased. Close monitoring of glycaemic control should be considered (see section 4.4).

Clinically significant interactions with CYP2C9 substrates or inhibitors are not anticipated.

Concomitant administration of rosiglitazone with the oral antihyperglycaemic agents glibenclamide and acarbose did not result in any clinically relevant pharmacokinetic interactions.

No clinically relevant interactions with digoxin, the CYP2C9 substrate warfarin, the CYP3A4 substrates nifedipine, ethinylestradiol or norethindrone were observed after co-administration with rosiglitazone.

Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis. Metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards and only after renal function has been re-evaluated and found to be normal.

Combination requiring precautions for use

Glucocorticoids (given by systemic and local routes) beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment. If necessary, the dosage of the antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

ACE-inhibitors may decrease the blood glucose levels. If necessary, the dosage of the antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

Rosiglitazone has been reported to cross the human placenta and to be detected in foetal tissues. For AVANDAMET no preclinical or clinical data on exposed pregnancies or lactation are available.

There are no adequate data from the use of rosiglitazone in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Therefore, AVANDAMET should not be used during pregnancy. If a patient wishes to become pregnant or if pregnancy occurs, treatment with AVANDAMET should be discontinued unless the expected benefit to the mother outweighs the potential risk to the foetus.

Both rosiglitazone and metformin have been detected in the milk of experimental animals. It is not known whether breast-feeding will lead to exposure of the infant to the medicinal product. AVANDAMET must therefore not be used in women who are breast-feeding (see section 4.3).

AVANDAMET has no or negligible influence on the ability to drive and use machines.

Adverse reactions are presented below for each of the component parts of AVANDAMET. An adverse reaction is only presented for the fixed dose combination if it has not been seen in one of the component parts of AVANDAMET or if it occurred at a higher frequency than that listed for a component part.

Adverse reactions for each treatment regimen are presented below by system organ class and absolute frequency. For dose-related adverse reactions the frequency category reflects the higher dose of rosiglitazone. Frequency categories do not account for other factors including varying study duration, pre-existing conditions and baseline patient characteristics. Adverse reaction frequency categories assigned based on clinical trial experience may not reflect the frequency of adverse events occurring during normal clinical practice. Frequencies are defined as: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1000) and very rare (<1/10,000 including isolated reports).

AVANDAMET

Data from double-blind studies confirm that the safety profile of concomitant rosiglitazone and metformin is similar to that of the combined adverse reaction profile for the twomedicinal products. Data with AVANDAMET is also consistent with this combined adverse reaction profile.

Clinical trial data (addition of insulin to established AVANDAMET therapy)

In a single study (n=322) where insulin was added to patients established on AVANDAMET, no new adverse events were observed in excess of those already defined for either AVANDAMET or rosiglitazone combination therapies.

However, the risk of both fluid related adverse events and hypoglycaemia are increased when AVANDAMET is used in combination with insulin.

Rosiglitazone

Clinical trial data

Adverse reactions for each treatment regimen are presented below by system organ class and absolute frequency. For dose-related adverse reactions the frequency category reflects the higher dose of rosiglitazone. Frequency categories do not account for other factors including varying study duration, pre-existing conditions and baseline patient characteristics.

Table 1 lists adverse reactions identified from an overview of clinical trials involving over 5,000 rosiglitazone-treated patients. Within each system organ class, adverse reactions are presented in the table by decreasing frequency for the rosiglitazone monotherapy treatment regimen. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. The frequency of adverse reactions identified from clinical trial data with rosiglitazone

*The frequency category for the background incidence of these events, as taken from placebo group data from clinical trials, is 'common'.

¹ Hypercholesterolaemia was reported in up to 5.3% of patients treated with rosiglitazone (monotherapy, dual or triple oral therapy). The elevated total cholesterol levels were associated with an increase in both LDLc and HDLc, but the ratio of total cholesterol:HDLc was unchanged or improved in long term studies. Overall, these increases were generally mild to moderate and usually did not require discontinuation of treatment.

² An increased incidence of heart failure has been observed when rosiglitazone was added to treatment regimens with a sulphonylurea (either as dual or triple therapy), and appeared higher with 8 mg rosiglitazone compared to 4 mg rosiglitazone (total daily dose). The incidence of heart failure on triple oral therapy was 1.4% in the main double blind study, compared to 0.4% for metformin plus sulphonylurea dual therapy. The incidence of heart failure in combination with insulin (rosiglitazone added to established insulin therapy) was 2.4%, compared to insulin alone, 1.1%.

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)]. To 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.

Table 2. The frequency of adverse reactions identified from post-marketing data with rosiglitazone

⁵Rare cases of elevated liver enzymes and hepatocellular dysfunction have been reported. In very rare cases, a fatal outcome has been reported.

Metformin

Clinical Trial Data and Post-marketing data

Table 3 presents adverse reactions by system organ class and by frequency category. Frequency categories are based on information available from metformin Summary of Product Characteristics available in the EU.

Table 3. The frequency of metformin adverse reactions identified from clinical trial and post-marketing data

⁶ Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.

⁷ Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g. megaloblastic anaemia).

No data are available with regard to overdose of AVANDAMET.

Limited data are available with regard to overdose of rosiglitazone in humans. In clinical studies in volunteers rosiglitazone has been administered at single oral doses of up to 20 mg and was well tolerated.

A large overdose of metformin (or coexisting risks of lactic acidosis) may lead to lactic acidosis which is a medical emergency and must be treated in hospital.

In the event of an overdose, it is recommended that appropriate supportive treatment is initiated as dictated by the patient's clinical status. The most effective method to remove lactate and metformin is haemodialysis, however rosiglitazone is highly protein bound and is not cleared by haemodialysis.

Pharmacotherapeutic group: Combinations of oral blood glucose loweringmedicinal products, ATC code: A10BD03

AVANDAMET combines two antihyperglycaemic agents with complimentary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: rosiglitazone maleate, a member of the thiazolidinedione class and metformin hydrochloride, a member of the biguanide class. Thiazolidinediones act primarily by reducing insulin resistance and biguanides act primarily by decreasing endogenous hepatic glucose production.

Rosiglitazone

Rosiglitazone is a selective agonist at the PPARγ (peroxisome proliferator activated receptor gamma) nuclear receptor and is a member of the thiazolidinedione class of antihyperglycaemic agents. It reduces glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver.

The antihyperglycaemic activity of rosiglitazone has been demonstrated in a number of animal models of type 2 diabetes. In addition, rosiglitazone preserved ß-cell function as shown by increased pancreatic islet mass and insulin content and prevented the development of overt hyperglycaemia in animal models of type 2 diabetes. Rosiglitazone did not stimulate pancreatic insulin secretion or induce hypoglycaemia in rats and mice. The major metabolite (a para-hydroxy-sulphate) with high affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in obese mice. The clinical relevance of this observation has not been fully elucidated.

In clinical trials, the glucose lowering effects observed with rosiglitazone are gradual in onset with near maximal reductions in fasting plasma glucose (FPG) evident following approximately 8 weeks of therapy. The improved glycaemic control is associated with reductions in both fasting and post-prandial glucose.

Rosiglitazone was associated with increases in weight. In mechanistic studies, the weight increase was predominantly shown to be due to increased subcutaneous fat with decreased visceral and intra-hepatic fat.

Consistent with the mechanism of action, rosiglitazone in combination with metformin reduced insulin resistance and improved pancreatic ß-cell function. Improved glycaemic control was also associated with significant decreases in free fatty acids. As a consequence of different but complementary mechanisms of action, combination therapy of rosiglitazone with metformin resulted in additive effects on glycaemic control in type 2 diabetic patients.

In studies with a maximal duration of three years, rosiglitazone given once or twice daily in dual oral therapy with metformin produced a sustained improvement in glycaemic control (FPG and HbA1c). A more pronounced glucose-lowering effect was observed in obese patients. An outcome study has not been completed with rosiglitazone, therefore the long-term benefits associated with improved glycaemic control of rosiglitazone have not been demonstrated.

An active controlled clinical trial (rosiglitazone up to 8 mg daily or metformin up to 2,000 mg daily) of 24 weeks duration was performed in 197 children (10-17 years of age) with type 2 diabetes. Improvement in HbA1c from baseline achieved statistical significance only in the metformin group. Rosiglitazone failed to demonstrate non-inferiority to metformin. Following rosiglitazone treatment, there were no new safety concerns noted in children compared to adult patients with type 2 diabetes mellitus. No long-term efficacy and safety data are available in paediatric patients.

ADOPT (A Diabetes Outcome Progression Trial) was a multicentre, double-blind, controlled trial with a treatment duration of 4-6 years (median duration of 4 years), in which rosiglitazone at doses of 4 to 8 mg/day was compared to metformin (500 mg to 2000 mg/day) and glibenclamide (2.5 to 15 mg/day) in 4351 drug naive subjects recently diagnosed (3 years) with type 2 diabetes. Rosiglitazone treatment significantly reduced the risk of reaching monotherapy failure (FPG >10.0 mmol/L) by 63% relative to glibenclamide (HR 0.37, CI 0.30-0.45) and by 32% relative to metformin (HR 0.68, CI 0.55-0.85) during the course of the study (up to 72 months of treatment). This translates to a cumulative incidence of treatment failure of 10.3% for rosiglitazone, 14.8% for metformin and 23.3% for glibenclamide treated patients. Overall, 43%, 47% and 42% of subjects in the rosiglitazone, glibenclamide and metformin groups respectively withdrew due to reasons other than monotherapy failure. The impact of these findings on disease progression or on microvascular or macrovascular outcomes has not been determined (see section 4.8). In this study, the adverse events observed were consistent with the known adverse event profile for each of the treatments, including continuing 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:

*Similar relative effective doses (i.e approximately half maximal dose) for other sulphonylureas (glibenclamide and glicazide).

† Patients who took designated treatment as randomised in combination with the correct background treatment and with evaluable data.

No difference in the number of adjudicated primary endpoint events for rosiglitazone (321/2220) versus active control (323/2227) (HR 0.99, CI 0.85-1.16) was observed, meeting the pre-defined non-inferiority criterion of 1.20 (non-inferiority p = 0.02). HR and CI for key secondary endpoints were: all-cause death (HR 0.86, CI 0.68-1.08), MACE (Major Adverse Cardiac Events - cardiovascular death, acute myocardial infarction, stroke) (HR 0.93, CI 0.74-1.15), cardiovascular death (HR 0.84, CI 0.59-1.18), acute myocardial infarction (HR 1.14, CI 0.80-1.63) and stroke (HR 0.72, CI 0.49-1.06). In a sub-study at 18 months, add-on rosiglitazone dual therapy was non-inferior to the combination of sulphonylurea plus metformin for lowering HbA1c. In the final analysis at 5 years, an adjusted mean reduction from baseline in HbA1c of 0.14% for patients on rosiglitazone added to metformin versus an increase of 0.17% for patients taking sulphonylurea added to metformin was seen during treatment with randomised dual-combination therapy (p<0.0001 for treatment difference). An adjusted mean reduction in HbA1c of 0.24% was seen for patients taking rosiglitazone added to sulphonylurea, versus a reduction in HbA1c of 0.10% for patients taking metformin added to sulphonylurea, (p=0.0083 for treatment difference). There was a significant increase in heart failure (fatal and non-fatal) (HR 2.10, CI 1.35-3.27) and bone fractures (Risk Ratio 1.57, CI 1.26-1.97) in rosiglitazone-containing treatments compared to active control (see sections 4.4 and 4.8). A total of 564 patients withdrew from cardiovascular follow-up, which accounted for 12.3% of rosiglitazone patients and 13% of control patients; representing 7.2% of patient-years lost for cardiovascular events follow-up and 2.0% of patient-years lost for all cause mortality follow-up.

Metformin

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

Metformin may act via three mechanisms:

- by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis

- in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilisation

- by delaying intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Metformin increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).

In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels.

The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:

- a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034

- a significant reduction of the absolute risk of diabetes-related mortality: metformin 7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017

- a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021)

- a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years (p=0.01).

AVANDAMET

Absorption

No statistically significant difference was observed between the absorption characteristics of rosiglitazone and metformin from the AVANDAMET tablet and those obtained from rosiglitazone maleate and metformin hydrochloride tablets, respectively.

Food had no effect on the AUC of rosiglitazone or metformin when AVANDAMET was administered to healthy volunteers. In the fed state, C_max was lower (22% rosiglitazone and 15% metformin) and t_max delayed (by approximately 1.5 h rosiglitazone and 0.5 h metformin). This food-effect is not considered clinically significant.

The following statements reflect the pharmacokinetic properties of the individual active substances of AVANDAMET.

Rosiglitazone

Absorption

Absolute bioavailability of rosiglitazone following both a 4 and an 8 mg oral dose is approximately 99%. Rosiglitazone plasma concentrations peak at around 1 h after dosing. Plasma concentrations are approximately dose proportional over the therapeutic dose range.

Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), although a small decrease in C_max (approximately 20-28%) and a delay in t_max (approximately 1.75 h) were observed compared to dosing in the fasting state. These small changes are not clinically significant and, therefore, it is not necessary to administer rosiglitazone at any particular time in relation to meals. The absorption of rosiglitazone is not affected by increases in gastric pH.

Distribution

The volume of distribution of rosiglitazone is approximately 14 l in healthy volunteers. Plasma protein binding of rosiglitazone is high (approximately 99.8%) and is not influenced by concentration or age. The protein binding of the major metabolite (a para-hydroxy-sulphate) is very high (> 99.99%).

Metabolism

Metabolism of rosiglitazone is extensive with no parent compound being excreted unchanged. The major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with sulphate and glucuronic acid. The contribution of the major metabolite (a para-hydroxy-sulphate) to the overall antihyperglycaemic activity of rosiglitazone has not been fully elucidated in man and it cannot be ruled out that the metabolite may contribute to the activity. However, this raises no safety concern regarding target or special populations as hepatic impairment is contraindicated and the phase III clinical studies included a considerable number of elderly patients and patients with mild to moderate renal impairment.

In vitro studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor contribution by CYP2C9.

Since there is no significant in vitro inhibition of CYP1A2, 2A6, 2C19, 2D6, 2E1, 3A or 4A with rosiglitazone, there is a low probability of significant metabolism-based interactions with substances metabolised by these P450 enzymes. Rosiglitazone showed moderate inhibition of CYP2C8 (IC₅₀ 18 µM) and low inhibition of CYP2C9 (IC₅₀ 50 µM) in vitro (see section 4.5). An in vivo interaction study with warfarin indicated that rosiglitazone does not interact with CYP2C9 substrates in vivo.

Elimination

Total plasma clearance of rosiglitazone is around 3 l/h and the terminal elimination half-life of rosiglitazone is approximately 3-4 h. There is no evidence for unexpected accumulation of rosiglitazone after once or twice daily dosing. The major route of excretion is the urine with approximately two-thirds of the dose being eliminated by this route, whereas faecal elimination accounts for approximately 25% of dose. No intact active substance is excreted in urine or faeces. The terminal half-life for radioactivity was about 130 h indicating that elimination of metabolites is very slow. Accumulation of the metabolites in plasma is expected upon repeated dosing, especially that of the major metabolite (a para-hydroxy-sulphate) for which an 8-fold accumulation is anticipated.

Special populations

Gender: In the pooled population pharmacokinetic analysis, there were no marked differences in the pharmacokinetics of rosiglitazone between males and females.

Elderly: In the pooled population pharmacokinetic analysis, age was not found to influence the pharmacokinetics of rosiglitazone to any significant extent.

Children and adolescents: Population pharmacokinetic analysis including 96 paediatric patients aged 10 to 18 years and weighing 35 to 178 kg suggested similar mean CL/F in children and adults. Individual CL/F in the paediatric population was in the same range as individual adult data. CL/F seemed to be independent of age, but increased with weight in the paediatric population.

Hepatic impairment: In cirrhotic patients with moderate (Child-Pugh B) hepatic impairment, unbound C_max and AUC were 2- and 3-fold higher than in normal subjects. The inter-subject variability was large, with a 7-fold difference in unbound AUC between patients.

Renal insufficiency: There are no clinically significant differences in the pharmacokinetics of rosiglitazone in patients with renal impairment or end stage renal disease on chronic dialysis.

Metformin

Absorption

After an oral dose of metformin, t_max is reached in 2.5 h. Absolute bioavailability of a 500 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.

After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 1 µg/ml. In controlled clinical trials, maximum metformin plasma levels (C_max) did not exceed 4 µg/ml, even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min prolongation of time to peak plasma concentration was observed. The clinical relevance of this decrease is unknown.

Distribution

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean V_d ranged between 63 – 276 l.

Metabolism

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination

Renal clearance of metformin is> 400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

No animal studies have been conducted with the combined products in AVANDAMET. The following data are findings in studies performed with rosiglitazone or metformin individually.

Rosiglitazone

Undesirable effects observed in animal studies with possible relevance to clinical use were as follows: An increase in plasma volume accompanied by decrease in red cell parameters and increase in heart weight. Increases in liver weight, plasma ALT (dog only) and fat tissue were also observed. Similar effects have been seen with other thiazolidinediones.

In reproductive toxicity studies, administration of rosiglitazone to rats during mid-late gestation was associated with foetal death and retarded foetal development. In addition, rosiglitazone inhibited ovarian oestradiol and progesterone synthesis and lowered plasma levels of these hormones resulting in effects on oestrus/menstrual cycles and fertility (see section 4.4).

In an animal model for familial adenomatous polyposis (FAP), treatment with rosiglitazone at 200 times the pharmacologically active dose increased tumour multiplicity in the colon. The relevance of this finding is unknown. However, rosiglitazone promoted differentiation and reversal of mutagenic changes in human colon cancer cells in vitro. In addition, rosiglitazone was not genotoxic in a battery of in vivo and in vitro genotoxicity studies and there was no evidence of colon tumours in lifetime studies of rosiglitazone in two rodent species.

Metformin

Non-clinical data for metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Tablet-core:

Sodium starch glycollate, hypromellose (E464), microcrystalline cellulose (E460), lactose monohydrate, povidone (E1201), magnesium stearate.

Avandamet 2 mg/1000 mg film-coating:

Hypromellose (E464), titanium dioxide (E171), macrogol, iron oxide yellow (E172).

Avandamet 2 mg/500 mg and Avandamet 4 mg/1000 mg film-coating:

Hypromellose (E464), titanium dioxide (E171), macrogol, iron oxide red (E172).

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Avandamet 2 mg/500 mg tablets:

Opaque blisters (PVC/PVdC/aluminium). Packs of 112 tablets.

Avandamet 2 mg/1000 mg and 4 mg/1000 mg tablets:

Opaque blisters (PVC/PVdC/aluminium). Packs of 56 tablets.

Any unused product should be disposed of in accordance with local requirements.

SmithKline Beecham Ltd.

980 Great West Road

Brentford, Middlesex

TW8 9GS

United Kingdom

EU/1/03/258/006 – Avandamet 2 mg/500 mg – 112 film-coated tablets.

EU/1/03/258/009 – Avandamet 2 mg/1000 mg – 56 film coated tablets

EU/1/03/258/012 – Avandamet 4 mg/1000 mg – 56 film-coated tablets

Date of First Authorisation:

20 October 2003 - Avandamet 2 mg/500 mg

02 September 2004 – Avandamet 2 mg/1000 mg

02 September 2004 – Avandamet 4 mg/1000 mg

Date of latest renewal: 08 August 2008 (all presentations)

01 April 2010