PPAR gamma agonists (peroxisomal proliferator activated receptor gamma agonists).

Rosiglitazone

AVANDIA 4 mg film-coated tablets. AVANDIA 8 mg film-coated tablets.

Film-coated tablet. AVANDIA 4 mg – orange film-coated tablets debossed with “GSK” on one side and "4" on the other side. AVANDIA 8 mg – Red-brown film-coated tablets debossed with “GSK” on one side and "8" on the other side.

Rosiglitazone is indicated in the treatment of type 2 diabetes mellitus:

as monotherapy

– in patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance

as dual oral therapy in combination with

– metformin, in patients (particularly overweight patients) with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin

– a sulphonylurea, only in patients who show intolerance to metformin or for whom metformin is contraindicated, with insufficient glycaemic control despite monotherapy with a sulphonylurea

as triple oral therapy in combination with

– metformin and a sulphonylurea, in patients (particularly overweight patients) with insufficient glycaemic control despite dual oral therapy.

Experience from clinical trials with rosiglitazone is currently limited to three years. The long-term benefits of therapy with rosiglitazone have not been demonstrated.

Rosiglitazone therapy is usually initiated at 4 mg/day. This dose canbe increased to 8 mg/day after eight weeks if greater glycaemic control is required. In patients administered rosiglitazone in combination with a sulphonylurea, an increase in rosiglitazone 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.

Rosiglitazone may be given once or twice a day.

Rosiglitazone may be taken with or without food.

Patients with renal impairment

No dose adjustment is required in patients with mild and moderate renal insufficiency. 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.

Patients with hepatic impairment

Rosiglitazone should not be used in patients with hepatic impairment.

There are no data available on the use of rosiglitazone in patients under 10 years of age. For children aged 10 to 17 years, there are limited data on rosiglitazone as monotherapy. The available data do not support efficacy in the paediatric population and therefore such use is not recommended.

Use of rosiglitazone is contraindicated in patients with:

− known hypersensitivity to rosiglitazone or to any of the excipients

− cardiac failure or history of cardiac failure (NYHA class I to IV)

− an Acute Coronary Syndrome (unstable angina, NSTEMI and STEMI)

− hepatic impairment.

− diabetic ketoacidosis and diabetic pre-coma.

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

The available data indicate that treatment with rosiglitazone may be associated with an increased risk of myocardial ischaemic events. 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.

Monitoring of liver function

There have been rare reports of hepatocellular dysfunction during post-marketing experience. 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. 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

In a long-term study an increased incidence of bone fractures (foot, hand and arm) was observed in female patients taking rosiglitazone as monotherapy. This increased incidence was noted after the first year of treatment and remained during the course of the study. 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, 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.

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.

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.

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.

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.

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 integrated clinical trial population of 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.

³In 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, 1.99% versus combined active and placebo comparators, 1.51% [Hazard ratio 1.31 (95% confidence interval 1.01 - 1.70)]. This risk was increased when rosiglitazone was added to established insulin and in patients receiving nitrates for known ischaemic heart disease. In a large observational study where patients were well-matched at baseline, the incidence of the composite endpoint myocardial infarction and coronary revascularization was 17.46 events per 1000 person years for rosiglitazone containing regimens and 17.57 events per 1000 person years for other anti-diabetic agents [Hazard ratio 0.93 (95% confidence interval 0.80 - 1.10)]. Three large long-term prospective randomised controlled clinical trials (mean duration 41 months; 14,067 patients), comparing rosiglitazone to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischaemia are inconclusive.

⁴ In a long-term randomised (4 to 6 year) monotherapy study in recently diagnosed patients with type 2 diabetes mellitus, an increased incidence of bone fractures was noted after the first year of treatment in female patients taking rosiglitazone (9.3%, 2.7 patients per 100 patient years) vs metformin (5.1%, 1.5 patients per 100 patient years) or glyburide/glibenclamide (3.5%, 1.3 patients per 100 patient years). This increased risk remained during the course of the study. The majority of the fractures in the females who received rosiglitazone were reported in the foot, hand and arm.

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

GlaxoSmithKline(GSK)

(POM)

26 June 2009