Rosiglitazone

An inhibitor of CYP2C8 (e.g., gemfibrozil) may increase the AUC of rosiglitazone and an inducer of CYP2C8 (e.g., rifampin) may decrease the AUC of rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response

Limited data are available in patients with severe renal insufficiency (creatinine clearance <30 ml/min) and therefore rosiglitazone should be used with caution in these patients.

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.

In patients with low haemoglobin levels before initiating therapy, there is an increased risk of anaemia during treatment with rosiglitazone.

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.

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. Rosiglitazone should not be used during pregnancy.

Rosiglitazone has been detected in the milk of experimental animals. It is not known whether breastfeeding will lead to exposure of the infant to drug. Rosiglitazone should therefore not be used in women who are breast-feeding.

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

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:

RSG – Rosiglitazone monotherapy; RSG + MET – Rosiglitazone with metformin; RSG + SU – Rosiglitazone with sulphonylurea; RSG + MET + SU – Rosiglitazone with metformin and sulphonylurea

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

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

² An increased incidence of heart failure has been observed when rosiglitazone was added to treatment regimens with a sulphonylurea (either as dual or triple therapy), and appeared higher with 8 mg rosiglitazone compared to 4 mg rosiglitazone (total daily dose). The incidence of heart failure on triple oral therapy was 1.4% in the main double blind study, compared to 0.4% for metformin plus sulphonylurea dual therapy. The incidence of heart failure in combination with insulin (rosiglitazone added to established insulin therapy) was 2.4%, compared to insulin alone, 1.1%. Moreover in patients with congestive heart failure NYHA class I-II, a placebo-controlled one-year trial demonstrated worsening or possible worsening of heart failure in 6.4% of patients treated with rosiglitazone, compared with 3.5% on placebo.

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

⁴ Long-term studies show an increased incidence of bone fracture in patients, particularly female patients, taking rosiglitazone. In a monotherapy study, the incidence in females for rosiglitazone was 9.3% (2.7 patients per 100 patient years) vs 5.1% (1.5 patients per 100 patient years) for metformin or 3.5% (1.3 patients per 100 patient years) for glibenclamide. In another long-term study, there was an increased incidence of bone fracture for subjects in the combined rosiglitazone group compared to active control [8.3% vs 5.3%, Risk ratio 1.57 (95% CI 1.26 – 1.97)]. The risk of fracture appeared to 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. Frequencies are defined as: rare ≥1/10,000, <1/1000 and very rare <1/10,000 including isolated reports.

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

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