Metformin and Rosiglitazone

For rosiglitazone/metformin no preclinical or clinical data on exposed pregnancies 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. The potential risk for humans is unknown.

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

For rosiglitazone/metformin no preclinical or clinical data on lactation are available.

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. Rosiglitazone/metformin combination must therefore not be used in women who are breast-feeding.

Rosiglitazone/metformin combination 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 rosiglitazone/metformin. An adverse reaction is only presented for the fixed dose combination if it has not been seen in one of the component parts 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).

Rosiglitazone/metformin

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 rosiglitazone/metformin is also consistent with this combined adverse reaction profile.

Clinical trial data (addition of insulin to established rosiglitazone/metformin therapy)

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

However, the risk of both fluid related adverse events and hypoglycaemia are increased when rosiglitazone/metformin 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.

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).