Drug Approvals
(British Approved Name Modified, US Adopted Name, rINN)
Adverse Effects and Precautions
Rosiglitazone may cause hypoglycaemia, headache, weight gain, and anaemia. It may also cause dizziness, gastrointestinal disturbances, muscle cramps and myalgia, dyspnoea, paraesthesia, pruritus, and hypercho-1 esterolaemia. Very rarely angioedema and urticaria have been reported. Rosiglitazone can also increase the risk of bone fracture in women. Rosiglitazone can cause oedema, which may worsen or precipitate heart failure. It should therefore be used with caution in patients with oedema, and should not be used in those with a history of heart failure (see also below). Renal impairment may increase the risk of fluid retention and heart failure. There have been very rare reports of new onset and worsening diabetic macular oedema with decreased visual acuity (see Effects on the Eyes, below). There is some evidence to suggest that rosiglitazone might increase the risk of myocardial ischaemia until further data become available, UK licensed product information advises that rosiglitazone is not recommended in patients with ischaemic heart disease or peripheral arterial disease (see also below). Liver function should be monitored periodically as there have been isolated reports of liver dysfunction, and the drug should be used with caution in patients with hepatic impairment (see Effects on the Liver, below).
In women who are anovulatory because of insulin resistance, rosiglitazone therapy may result in a resumption of ovulation.
Effects on the bones. Use of thiazolidinediones such as pioglitazone or rosiglitazone has been associated with decreases in bone mineral density and increased risk of fractures in female patients. Analysis of data from a comparative study of glycaemic control with rosiglitazone, metformin, or glibenclamide involving 4360 randomised patients found that the risk of fracture in female patients in these 3 groups was 9.3%, 5.1%, and 3.5% respectively the risk in male patients was not significantly different in the 3 groups at around 3.4 to 3.95%. Analysis of data from another large ongoing study was also consistent with an increased fracture risk with rosiglitazone, and data from the manufacturer of pioglitazone involving over 8100 treated patients also revealed an increased risk of fracture in women given the drug the excess risk was calculated to be 0.8 per 100 patient years of use. The pattern of fractures seems to differ from that associated with postmenopausal osteoporosis, being mainly in the upper arm, hand, or foot, rather than hip or spine, but an observational study has suggested that thiazolidinedione use is associated with ongoing loss of whole-body bone mineral density.
Effects on the cardiovascular system. It has been suggested that, in addition to their hypoglycaemic effect, thiazolidinediones may have beneficial effects in the prevention of macrovascular diabetic complications, and there is some evidence that pioglitazone may improve some cardiovascular outcomes (see Diabetic Complications). However, a meta-analysis of 42 studies found that, compared with either placebo or other antidiabetic drugs, rosiglitazone was associated with a significant increase in the risk of myocardial infarction, and an increase of borderline significance in death from cardiovascular causes. There were limitations to this analysis as the studies were not primarily intended to examine cardiovascular outcomes, and many were small and short-term. Another meta-analysis that was restricted to 4 long-term studies (at least 12 months of treatment) that had specified an intention to evaluate cardiovascular adverse effects also found an increased risk of myocardial infarction with rosiglitazone use, without a significant increase in the risk of cardiovascular mortality.
Studies with no recorded cardiovascular events were excluded from the larger meta-analysis, and this has been questioned. An alternative analysis that incorporated these excluded studies, with appropriate analysis adjustment, found odds ratios for myocardial infarction and cardiovascular death that were not statistically significant, and concluded that neither increased nor decreased risk could be established.
In response to concerns raised by the initial meta-analysis, an unplanned interim analysis of an ongoing open-label study designed to assess cardiovascular outcomes has been published (rosiglitazone added to either metformin or a sulfonylurea compared with metformin plus a sulfonylurea) The data, however, were insufficient to determine whether there was an increased risk of myocardial infarction, and the findings were inconclusive regarding any effect on overall risks of hospitalisation or death from cardiovascular causes.
For the risks of heart failure associated with thiazolidinediones, see Effects on the Heart, below.
Effects on the eyes. The manufacturers in the USA and Canada (GSK) have received postmarketing reports of the development or worsening of diabetic macular oedema in patients treated with rosiglitazone-containing products in most cases the patients also reported peripheral oedema or fluid retention. In some cases visual impairment improved or resolved after stopping the drug. Rosiglitazone should be used with caution in patients with pre-existing diabetic retinopathy or macular oedema, and should be stopped, and ophthalmological consultation sought, if visual impairment develops while using the drug.
Effects on the heart. Both pioglitazone and rosiglitazone can cause peripheral and pulmonary oedema, which can worsen or precipitate heart failure a number of cases have been described. A large retrospective cohort study also found that the use of thiazolidinediones increased the risk of heart failure. The incidence of peripheral oedema with monotherapy has been reported to range from 3 to 5%, and this increases slightly when a thiazolidinedione is used with another oral antidiabetic. The incidence is about 15% when a thiazolidinedione is used with insulin. The incidence of heart failure is generally lower, but has been reported to be 2 to 3% when a thiazolidinedione is used with insulin however, a large prospective study, which was intended to examine the cardiovascular benefits of pioglitazone in preventing secondary macrovascular events in diabetic patients with pre-existing macrovascular disease, reported a 6% incidence of heart failure, compared with 4% in the placebo group. Mortality rates from heart failure did not differ between groups. These figures were confirmed on re-analysis.The American Heart Association and American Diabetes Association have recommended that patients with risk factors for heart disease or a depressed ejection fraction but without symptoms, and patients with NYHA class I or II heart failure, should start with a low dose of a thiazolidinedione that is only increased gradually as necessary and with careful monitoring. Patients with more severe heart failure (class III and IV) should not receive these drugs. These recommendations are reflected in US licensed product information. UK licensed product information contraindicates the use of pioglitazone or rosiglitazone in patients with heart failure or any history of heart failure, even of class I or II. For restrictions on combination therapy see Administration, below.
Effects on lipids. Rosiglitazone and pioglitazone have different effects on serum lipids.
Effects on the liver. Several cases of hepatotoxicity have been described in patients receiving rosiglitazone. Most of these occurred within a few weeks or months of starting rosiglitazone therapy. However, the causality of some of these cases has been debated’ because of coexisting disease and concomitant medication.
Licensed product information recommends that liver enzymes should be checked before starting therapy with rosiglitazone patients with aminotransferase (ALT) concentrations more than 2.5 times the upper limit of normal should not be given rosiglitazone. ALT concentrations should then be monitored periodically. If aminotransferase concentrations rise to more than 3 times the upper limit of normal and remain so after retesting then treatment with rosiglitazone should be stopped treatment should also be stopped if jaundice develops.
Fasting. For mention that glitazones can probably be used with low risk of hypoglycaemia in fasting Muslim patients during Ramadan see under Precautions of Insulin.
Interactions
Gemfibrozil, ketoconazole, and trimethoprim, can increase plasma concentrations of rosiglitazone. Conversely, rifampicin can reduce rosiglitazone concentrations. These drugs should be given with caution to patients taking rosiglitazone, and glycaemic control should be monitored.
Use of NSAIDs or insulin with rosiglitazone may increase the risk of oedema and heart failure (see also Effects on the Heart, above, and Administration, below).
Antibacterials. Rifampicin significantly reduced the plasma concentration and elimination half-life of rosiglitazone in studies’ of healthy subjects, probably by induction of the cytochrome P450 isoenzyme CYP2C8. Conversely, trimethoprim can inhibit CYP2C8, and was found to increase the concentration and half-life of rosiglitazone modestly.’
Antifungals. In a study of healthy subjects, ketoconazole increased the plasma concentration and elimination half-life of rosiglitazone, probably by inhibition of the cytochrome P450 isoenzyme CYP2C8 and to a lesser extent CYP2C9
Lipid regulating drugs. Gemfibrozil increased the plasma concentration and about doubled the half-life of rosiglitazone in a study of healthy subjects, probably by inhibiting its metabolism. The authors suggested that these drugs should not be used together, or that the dose of rosiglitazone should be at least halved if gemfibrozil treatment is started.
Pharmacokinetics
Rosiglitazone is well absorbed from the gastrointestinal tract after oral dosing. Peak plasma concentrations occur within 1 hour and the bioavailability is 99%. It is 99.8% bound to plasma proteins. Rosiglitazone is extensively metabolised, almost exclusively by the cytochrome P450 isoenzyme CYP2C8. It is excreted in the urine and faeces, and has a half-life of 3 to 4 hours.
Uses and Administration
Rosiglitazone is a thiazolidinedione oral antidiabetic that improves insulin sensitivity and is used for the treatment of type 2 diabetes mellitus. It is usually given as rosiglitazone maleate but doses are expressed in terms of the base rosiglitazone maleate 1.32 mg is equivalent to about 1 mg of rosiglitazone. The potassium salt is used in some countries. Rosiglitazone is given orally as monotherapy, particularly in patients who are overweight and for whom metformin is contra-indicated or not tolerated. It may also be added to metformin, a sulfonylurea (or a combination of the two), or to insulin, when such therapy is inadequate (but see Administration, below). The usual initial dose is 4 mg daily, given in a single dose or two divided doses. The dose may be increased to a maximum of 8 mg daily if necessary after 8 to 12 weeks in patients receiving monotherapy or combination oral therapy. Rosiglitazone may be taken with or without food.
Administration. Although rosiglitazone is licensed for use with other antidiabetic drugs the specifics of licensing and use may vary from country to country. In both the UK and USA, rosiglitazone (Avandia GSK) is licensed for use with metformin or a sulfonylurea, or both if necessary, in patients in whom single or dual agent therapy is inadequate. In the UK, however, NICE recommends dual therapy only in patients who cannot be given combination therapy with metformin plus a sulfonylurea.The combination of rosiglitazone with insulin is now generally avoided because of an increased risk of heart failure and other cardiac adverse events (see also Effects on the Heart, above), although licensed product information may not necessarily contra-indicate the combination. In the UK, licensed product information for rosiglitazone warns that insulin should only be added to established rosiglitazone therapy in exceptional cases and under close supervision. In the USA, the combination of rosiglitazone and insulin is not recommended.
Inflammatory bowel disease. There is some evidence to suggest that drugs such as rosiglitazone that act as ligands to peroxisome proliferator-activated receptor y (PPARy) may offer a novel therapeutic approach to management of inflammatory bowel disease.
Polycystic ovary syndrome. Insulin resistance is a feature of polycystic ovary syndrome and the use of rosiglitazone is under investigation.
Preparations
Proprietary Preparations
Argentina: Avandia Diaben Gaudil Glimide Gliximina Gludex Rosiglit
Australia: Avandia
Belgium: Avandia
Brazil: Avandia
Canada: Avandia
Chile: Avandia
Czech Republic: Avandia
Denmark: Avandia
Finland: Avandia
France: Avandia
Germany: Avandia
Greece: Avandia
Hong Kong: Avandia
Hungary: Avandia
India: Rezult † Roglin Rosicon
Indonesia: Avandia
Ireland: Avandia
Israel: Avandia
Italy: Avandia
Malaysia: Avandia
Mexico: Avandia
The Netherlands: Avandia
Norway: Avandia
New Zealand: Avandia
Philippines: Avandia
Poland: Avandia
Portugal: Avandia
Russia: Avandia Roglit
South Africa: Avandia
Singapore Avandia
Spain: Avandia
Sweden: Avandia
Switzerland: Avandia
Thailand: Avandia
Turkey: Avandia
UK: Avandia
USA: Avandia
Venezuela: Avandia
Multi-ingredient
Argentina: Avandamet Gludex Plus Rosiglit-Met
Australia: Avandamet
Belgium: Avandamet
Canada: Avandamet
Chile: Avandamet
Czech Republic: Avaglim Avandamet
Denmark: Avandamet
Finland: Avandamet
France: Avaglim Avandamet
Germany: Avandamet
Greece: Avaglim Avandamet
Hong Kong: Avandamet
Hungary: Avaglim Avandamet
India: Glyroz Roglin-M Rosicon M †
Indonesia: Avandamet Avandaryl
Ireland: Avandamet
Israel: Avandamet
Italy: Avandamet
Malaysia: Avandamet
Mexico: Avandamet
The Netherlands: Avandamet
Norway: Avandamet
Philippines: Avandamet
Poland: Avandamet
Portugal: Avaglim Avandamet
Singapore: Avandamet
Spain: Avandamet
Sweden: Avandamet
Switzerland: Avandamet
Thailand: Avandamet
UK: Avandamet
USA: Avandamet Avandaryl
Venezuela: Avandamet