AVANDAMET Film-coated tablet Ref.[51379] Active ingredients: Metformin Metformin and Rosiglitazone Rosiglitazone

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 dose-related hypoglycaemia. Increased monitoring of the patient and a reduction in the dose of the concomitant agent may be necessary.

Surgery

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

Administration of iodinated contrast agent

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

Bone disorders

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

Other precautions

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

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

All patients should continue their diet with regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet. The usual laboratory tests for diabetes monitoring should be performed regularly.

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

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

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

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

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

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

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.

For AVANDAMET no preclinical or clinical data on exposed pregnancies or lactation are available.

Rosiglitazone has been reported to cross the human placenta and to be detectable in foetal tissues. There are no adequate data from the use of rosiglitazone in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

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

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

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

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

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

AVANDAMET

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

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

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

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

Rosiglitazone

Clinical trial data

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

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

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%.

In a placebo-controlled one-year trial in patients with congestive heart failure NYHA class I-II, worsening or possible worsening of heart failure occurred in 6.4% of patients treated with rosiglitazone, compared with 3.5% on placebo.

³ In a retrospective analysis of data from 42 pooled short-term clinical studies, the overall incidence of events typically associated with cardiac ischaemia was higher for rosiglitazone containing regimens, 2.00% versus combined active and placebo comparators, 1.53% [hazard ratio (HR) 1.30 (95% confidence interval (CI) 1.004-1.69)]. This risk was increased when rosiglitazone was added to established insulin and in patients receiving nitrates for known ischaemic heart disease. In an update to this retrospective analysis that included 10 further studies that met the criteria for inclusion, but were not available at the time of the original analysis, the overall incidence of events typically associated with cardiac ischaemia was not statistically different for rosiglitazone containing regimens, 2.21% versus combined active and placebo comparators, 2.08% [HR 1.098 (95% CI 0.809-1.354)]. In a prospective cardiovascular outcomes study (mean follow-up 5.5 years) the primary endpoint events of cardiovascular death or hospitalisation were similar between rosiglitazone and active comparators [HR 0.99 (95% CI 0.85-1.16)]. Two other long-term prospective randomised controlled clinical trials (9,620 patients, study duration >3 years in each study), comparing rosiglitazone to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded the potential risk of cardiac ischaemia. In their entirety, the available data on the risk of cardiac ischaemia are inconclusive.

⁴ Long-term studies show an increased incidence of bone fracture in patients, particularly female patients, taking rosiglitazone. In a monotherapy study, the incidence in females for rosiglitazone was 9.3% (2.7 patients per 100 patient years) vs 5.1% (1.5 patients per 100 patient years) for metformin or 3.5% (1.3 patients per 100 patient years) for glibenclamide. In another long-term study, there was an increased incidence of bone fracture for subjects in the combined rosiglitazone group compared to active control [8.3% vs 5.3%, Risk ratio 1.57 (95% CI 1.26-1.97)]. The risk of fracture appeared to be higher in females relative to control [11.5% vs 6.3%, Risk ratio 1.82 (95% CI 1.37-2.41)], than in males relative to control [5.3% vs 4.3%, Risk ratio 1.23 (95% CI 0.85-1.77)]. Additional data are necessary to determine whether there is an increased risk of fracture in males after a longer period of follow-up. The majority of the fractures were reported in the upper limbs and distal lower limbs (see section 4.4).

In double-blind clinical trials with rosiglitazone the incidence of elevations of ALT greater than three times the upper limit of normal was equal to placebo (0.2%) and less than that of the active comparators (0.5% metformin/sulphonylureas). The incidence of all adverse events relating to liver and biliary systems was <1.5% in any treatment group and similar to placebo.

Post-marketing data

In addition to the adverse reactions identified from clinical trial data, the adverse reactions presented in Table 2 have been identified in post approval use of rosiglitazone.

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

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

Metformin

Clinical Trial Data and Post-marketing data

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

Table 3. The frequency of metformin adverse reactions identified from clinical trial and postmarketing 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).

Not applicable.