Tag Archives: Avandia
Oral agents for glucose management
Five classes of oral pharmaceutical agents for the treatment of type 2 diabetes have been approved in the United States by the Food and Drug Administration (FDA). In general, there is no clinical evidence of superiority of a particular drug over another in elderly patients. Knowledge of pharmacokinetics, side effects, and potential interactions allow for a safe use of these drugs in older patients with diabetes. Two classes of drugs, the sulfonylureas and the meglitinides improve glucose levels by stimulating insulin secretion from pancreatic β-cells. Other agents target different mechanisms in the underlying pathogenesis of the disease, such as the reduction of carbohydrate absorption (a-glucosidase inhibitors) and improvement in insulin sensitivity (biguanides and thiazolidinediones). Any of these agents may be used as first-line monotherapy since most demonstrate equivalent efficacy in improving glycemic control. When monotherapy fails, the addition of a second oral agent from a different drug class is advised to achieve fasting or postprandial glycemic targets. In general, the use of triple therapy is safe but should be used with caution because of the high risk of polypharmacy in the elderly and higher associated costs.
TABLE Noninsulin Agents for Treatment of Type 2 Diabetes
| Drug | Dosage | Efficacy (change in HbA1c) |
| Oral agents | ||
| Sulfonylureas (2nd generation) | -1 % to -2% | |
| Glimepiride (Amaryl) | 4-8 mg daily (begin 1-2 mg) | |
| Glipizide (Glucotrol) | 2.5-40 mg daily or divided | |
| (Glucotrol XL) | 5-20 mg daily | |
| Glyburide (Diapeta, Micronase) | 1.25-20 mg daily or divided | |
| Micronized glyburide (Glynase) | 1.5-12 mg daily | |
| Meglitinides | -1 % to -2% | |
| Nateglinide (Starlix) | 60-120 mg t.i.d. | |
| Repaglinide (Prandin) | 0.5 mg b.i.d.-q.i.d. if HbA1c < 8% or previously untreated | |
| 1-2 mg b.i.d.-q.i.d. if HbA1c >8% or previously treated | ||
| a-Glucosidase Inhibitors | -0.5% to-1% | |
| Acarbose(Precose) | 50-100 mg t.i.d., just before meals; start with 25 mg | |
| Miglitol (Glyset) | 25-100 mg t.i.d, with first bite of meal; start with 25 mg | |
| Biguanides | -1 % to -2% | |
| Metformin (Glucophage) | 500-2550 mg divided | |
| (Glucophage XR) | 1500-2000 mg daily | |
| Thiazolidinediones | -1 % to -2% | |
| Pioglitazone (Ados) | 15 or 30 mg daily; max 45 mg/day as monotherapy, 30 mg/day in combination therapy | |
| Rosiglitazone (Avandia) | 4 mg daily orb.i.d. | |
| Injectable agents | -0.5% to-1% | |
| Incretin mimetic | 5—10 µg s.c. b.i.d. | |
| Exenatide (Byetta) | ||
| Amylin analog | 60 µg s.c. before meals | |
| Pramlintide (Symlin) |
TABLE Mechanisms to Lower Blood Glucose by Each Antidiabetic Agent
| Correct
insulin deficiency |
Stimulate
insulin secretion |
Increase
muscle glucose uptake |
Decrease hepatic
glucose production |
Retard
carbohydrate absorption |
|
| Sulfonylureas | X | ||||
| Meglitinides | X | ||||
| Biguanides | (X) | X | |||
| Thiazolidinediones | X | (X) | |||
| Glucosidase inhibitors | X | ||||
| Incretin mimetics/amylin analogs | X | X | X | ||
| Insulin/insulin analogs | X |
Note: X, main mechanism; (X) less-clear mechanism.
Sulfonylurea preparations have a long record of safety and effectiveness. They work by stimulating insulin secretion by the pancreatic /3-cell, binding to an adenosine triphosphate-sensitive potassium channel, which results in its depolarization, a subsequent influx of intracellular calcium, and the release of insulin. Sulfonylureas are effective both as monotherapy and in combination with other agents that have different mechanisms of action. A significant percentage of patients (up to 10% per year) who are initially properly managed with sulfonylurea monotherapy lose glycemic control over time. Their main side effects include hypoglycemia and weight gain. Hypoglycemia is a serious adverse effect in the elderly and can trigger serious events such as myocardial infarction and stroke. These drugs must be used cautiously in patients with significant renal and hepatic insufficiency, since the liver is the primary site of metabolism and they are excreted by the kidneys. In these settings, the preferred option may be glipizide, whose metabolites are inactive, or glimepiride, which is substantially excreted through the bile.
A commonly used sulfonylurea in younger populations, glyburide, may have age-related impaired absorption and elimination, and elderly subjects appear to have enhanced insulin responses to the drug as well. This may explain, in part, the age-related exponential increase in the frequency of severe or fatal hypoglycemia with this drug.
TABLE Limiting Factors in the Use of Antidiabetic Agents in the Elderly
| Hypoglycemia | Weight gain | Other | |
| Sulfonylureas | X | X | May impede ischemic preconditioning |
| Meglitinides | X | X | Frequent dosing may affect compliance; no long-term experience |
| Biguanides | No | No (wt loss) | Risk of lactic acidosis; diarrhea |
| Thiazolidinediones | No | XX | Edema; expensive; no long-term experience |
| Glucosidase inhibitors | No | No | Frequent dosing may affect compliance; intestinal gas; expensive |
| Incretin mimetics/amylin analogs | No | No (wt loss) | Injection; expensive; no long-term experience |
May impede ischemic preconditioning Frequent dosing may affect compliance; no long-term experience Risk of lactic acidosis; diarrhea Edema; expensive; no long-term experience Frequent dosing may affect compliance; intestinal gas; expensive Injection; expensive; no long-term experience
Note: X, main side effect; XX, pronounced side effect. Abbreviation: wt, weight.
In addition to the type of sulfonylurea, other potential risk factors for hypoglycemia with these drugs in elderly persons include black race, multiple medications, male sex, renal dysfunction, and ethanol consumption. Sulfonylureas should be considered as first-line therapy in lean elderly patients with diabetes. The result in hemoglobin Ale (HbAlc) lowering is approximately 1% to 2% as monotherapy.
Meglitinides
Meglitinides (repaglinide and nateglinide) are nonsulfonylurea drugs that have a distinct β-cell binding profile and stimulate insulin secretion from the β-cell by a mechanism similar to that of sulfonylureas. The potential advantage of this type of drug is that it has a rapid onset and very short duration of action. Meglitinides have been associated with lower frequency of hypoglycemic events when compared with conventional sulfonylureas, presumably because of their shorter duration of action and the fact that the kinetics are not altered with age. Repaglinide lowers HbAlc by 1% to 2%, a reduction similar to that of the sulfonylureas, whereas the glucose-lowering effect of nateglinide is somewhat less potent. Similar changes in fasting glucose and HbAlc values are seen in middle-aged and elderly subjects, suggesting that there is similar efficacy in each age group. Both repaglinide and nateglinide are extensively metabolized by the liver; therefore, they should be used cautiously in patients with hepatic dysfunction. Meglitinides may be considered as an appropriate strategy for elderly patients who have irregular eating habits or have frequent hypoglycemic events on conventional sulfonylureas. These potential benefits must be balanced against the cost of these newer drugs and the compliance problems that could result from a three-times-a-day dosing schedule, particularly in patients who have impaired memory or take may other drugs.
α-Glucosidase Inhibitors
α-glucosidase inhibitors (miglitol and acarbose) impair the breakdown and limit the absorption of carbohydrates from the gut; therefore their major effect is reduction in postprandial glucose excursions. These drugs are associated with less weight gain and a lower frequency of hypoglycemia than sulfonylureas. The residual carbohydrates in the intestinal lumen cause diarrhea in about 25% of patients taking these drugs. Gradual dose titration is crucial to minimize gastrointestinal side effects and achieve better compliance. Their overall effect on HbAlc concentration is a modest reduction of 0.5% to 1%. In a recent randomized multicenter trial of the a-glucosidase inhibitor acarbose in obese elderly patients with diabetes, acarbose reduced HbAlc by about 0.8% when compared with placebo and also resulted in an improvement in insulin sensitivity. α-glucosidase inhibitors are useful drugs as primary therapy for elderly patients with modest fasting hyperglycemia, especially if they are obese. They can also be used in patients taking other oral agents to enhance glycemic control. Hypoglycemia may occur if these agents are used in combination with sulfonylureas or insulin; consequently, only glucose should be used for prompt treatment of hypoglycemia because the absorption of other carbohydrates is delayed. Acarbose has minimal systemic absorption, yet some hepatic metabolism occurs and because of rare but possible hepatotoxicity, it is contraindicated in patients with advanced liver disease. In contrast, as much as 50% to 90% of the miglitol dose may be absorbed but is not metabolized in the liver but rather eliminated through the kidney. Therefore, miglitol should not be used in patients with renal failure.
Metformin
Metformin is currently the only biguanide available in North America. Its mechanism of action is to improve insulin sensitivity, chiefly by reducing insulin resistance in the liver, thereby decreasing hepatic glucose production. In addition, its glucose-lowering effect is accompanied by a reduction in plasma insulin concentration, and some experts refer to metformin as an insulin sensitizer. Metformin lowers HbAlc by 1% to 2%. Although, the most important side effect associated with biguanides is lactic acidosis, this is rare with metformin; and aging itself does not appear to be a risk factor provided that careful attention is paid to the contraindications for this drug (significant liver, renal, and cardiac disease). Clinical studies suggest that the drug is safe and effective as monotherapy in obese older people. In our view, metformin is an ideal drug for first-line therapy of obese older patients, because it increases insulin sensitivity, assists with weight loss, reduces lipid levels, and does not cause hypoglycemia. The recently published ADA management algorithm suggests the use of metformin, together with lifestyle intervention, as initial monotherapy.
In addition, metformin is a useful adjunct for patients who are inadequately controlled on maximum doses of sulfonylureas. Metformin is contraindicated in older subjects with renal insufficiency, in men with a serum creatinine level of 1.5 mg/dL or higher or women with a serum creatinine level of 1.4 mg/dL or higher. Serum creatinine should be measured at least annually and with any increase in dose of metformin. It should be noted, however, that serum creatinine does not adequately reflect the renal function in the elderly. For those aged 80 years or older or those suspected to have reduced muscle mass, a timed urine collection for creatinine clearance should be obtained. Metformin should be avoided if the value is less than 60 mL/ min. Metformin should be temporarily discontinued during radiographic studies that use iodinated contrast agents, during acute illness, and during most hospitalizations. Clinical situations where tissue perfusion is compromised (sepsis, dehydration, pulmonary disease with hypoxemia, and acute or advanced heart failure) also contraindicate the use of metformin.
Thiazolidinediones
Thiazolidinediones (rosiglitazone and pioglitazone) improve insulin sensitivity primarily in muscles and adipocytes, thereby increasing peripheral uptake and utilization of glucose. They are generally well tolerated and appear to be as effective in older patients as in younger patients, with an approximate 1.5% reduction in HbAlc and with a dose-dependent glucose-lowering effect, which may take four to eight weeks. In addition to benefits of these drugs on cardiovascular and metabolic markers, a recent randomized trial has shown the effect of pioglitazone on the reduction of cardiovascular outcomes in patients with type 2 diabetes. Thiazolidinediones do not lead to hypoglycemia unless they are used in conjunction with secretagogues or insulin. Hepatic toxicity has not been reported in elderly subjects, but liver function tests should be monitored regularly. The incidence of edema and anemia is higher in elderly patients than in middle-aged patients treated, and volume status and blood count need to be carefully monitored. Thiazolidinediones-related fluid retention is a major contributor to increased body weight, typically manifests as peripheral edema, and develops predominantly within the first months of treatment. Thiazolidinediones can be a useful first-line therapy in obese elderly patients, particularly for those patients who cannot tolerate metformin or those who have a contraindication to it. In fact, thiazolidinediones can be safely used in patients with renal impairment provided that the cardiac function is preserved. In addition, they may be a beneficial adjunct therapy in elderly patients who have suboptimal glycemic control, despite insulin requirements of 50 or more units per day.
Diabetes drugs protect against heart disease
The medication rosiglitazone (Avandia) controls diabetics’ blood sugar by binding to the PPAR gamma receptor in fat cells, doctors have known. Now new research shows that these receptors also exist in arteries, where they may help protect against heart disease, Dr. Ronald E. Law and colleagues at the University of California at Los Angeles School of Medicine report in the March 21, 2000, Circulation. The study was a preclinical in vitro study using both human and rat tissue.
Previous studies had “been divided as to [the receptor's] presence in the artery wall,” although they did show that it existed in other types of tissue, Dr. Law said.
By binding to the artery receptors, the medication may lower diabetics’ risk of clogged arteries, including restenosis (when an artery is blocked again after angioplasty), the team reports. Rosiglitazone treats type 2 diabetes, which begins in adulthood, and not type 1, which usually begins in childhood.
If an artery is damaged even slightly, such as from atherosclerosis or after angioplasty, the tissue increases production of growth factors that cause cells in the area to multiply and migrate. Such cell activity is dangerous, because it can lead to artery walls getting thicker. However, when the researchers exposed artery smooth muscle cells to the diabetes medication, the cells failed to multiply or migrate, the team reports. The drugs may slow the build-up of fatty substances along the artery wall.
What the PPAR gamma receptor normally does other than bind with diabetes drugs is unclear, Dr. Law told Mediconsult. “We don’t really understand what normally turns these receptors on, or what their role is in tissue other than…to make more fat cells, he said.
The team also tested another diabetes drug, troglitazone (Rezulin), but it was taken off the market in March 2000, because of possible dangerous side effects. Both drugs are part of the thiazolidinedione (TZD) class of drugs that control blood sugar levels in people with type 2 diabetes.
Commenting on the study, Dr. Andrew P. Levy, M.D., Ph.D, at the Technion Faculty of Medicine, and Medical Advisor for HeartInfo, says that, “The new TZD drugs described above will help patients with type 2 control their glucose levels. The precise mechanism as to how these drugs achieve their effect is not entirely clear. More research is required to fully understand their mode of action, but their efficacy is indisputable.”
Rosiglitazone Maleate
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
Two Glitazones for Diabetes
An FDA advisory committee unanimously endorsed approval for marketing of rosiglitazone (Avandia, SmithKline Beecham) and concluded that pioglitazone (Actos, Takeda) is safe (the panel did not review efficacy of pioglitazone). Even though no cases of liver failure or toxicity have been reported with either drug, the panel recommended inclusion of warnings in their labeling that would suggest periodic liver tests because of problems with troglitazone (Rezulin, Parke-Davis).
Separately, SKB strengthened its hand by announcing it would copromote rosiglitazone – likely to be approved for treatment of patients with diabetes type 2 as either monotherapy or with metformin – with Bristol-Myers Squibb, which markets metformin (Glucophage). Since rosiglitazone will probably reach the U.S. market before pioglitazone, the collaboration could be critical in quickly penetrating the insulin-resistance market. Some experts project that pioglitazone will become the market leader in the glitazone class, and Takeda’s previously announced marketing collaboration with Lilly promises to make the competition fierce.
Rosiglitazone (Avandia) Approved for Type 2 DM
SmithKline Beecham’s rosiglitazone (Avandia) received approval from FDA for treatment of type 2 diabetes as either monotherapy or in combination with metformin. Since the agent has not produced liver toxicities in patients in clinical trials, it is expected to largely displace use of troglitazone when it is released in a few days. SKB is copromoting the product with Bristol-Myers Squibb.
FDA approval was based on clinical studies involving more than 5,500 patients with type 2 diabetes. In these studies, rosiglitazone effectively lowered blood glucose levels of patients by an average of 76 mg/dL, compared with placebo, and maintained blood glucose control for up to 12 months. Patients achieved an average reduction in hemoglobin A1C levels up to 1.5 percentage points at a daily dose of 8 mg, demonstrating a statistically significant improvement in glycemic control relative to placebo and also in comparison to baseline.
Commonly reported side effects with rosiglitazone were upper respiratory tract infections, headaches, anemia, and edema. As with other members of this class, weight gain has been reported.