AVANDIA Film-coated tablet Ref.[108135] Active ingredients: Rosiglitazone

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 or 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. Increased monitoring of the patient is recommended if rosiglitazone is used in combination with metformin and insulin. 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 (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 rosiglitazone in all patients and periodically thereafter based on clinical judgement. Therapy with rosiglitazone 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 rosiglitazone 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 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 rosiglitazone.

Hypoglycaemia

Patients receiving rosiglitazone in combination therapy with a sulphonylurea or with 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.

Triple oral therapy

The use of rosiglitazone in triple oral therapy, in combination with metformin and a sulphonylurea, may be associated with increased risks for fluid retention and heart failure, as well as hypoglycaemia (see section 4.8). Increased monitoring of the patient is recommended and adjustment of the dose of sulphonylurea may be necessary. The decision to initiate triple oral therapy should include consideration of the alternative to switch the patient to insulin.

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.

Others

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 and if a patient wishes to become pregnant or if pregnancy occurs the treatment should be discontinued (see section 4.6).

Rosiglitazone should be used with caution in patients with severe renal insufficiency (creatinine clearance <30 ml/min).

Rosiglitazone should be used with caution during concomitant administration of CYP2C8 inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely. Rosiglitazone dose adjustment within the recommended posology or changes in diabetic treatment should be considered (see section 4.5).

AVANDIA 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.

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 with the oral anti-diabetic agents metformin, glibenclamide and acarbose did not result in any clinically relevant pharmacokinetic interactions with rosiglitazone. Moderate ingestion of alcohol with rosiglitazone has no effect on glycaemic control.

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

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. 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.

AVANDIA 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 (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.

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.

Not applicable.