Antidiabetic Drugs

Posts Tagged ‘Avandia’

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

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.

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.

Brand Name: Avandia
Active Ingredient: rosiglitazone maleate
Indication: For the treatment of Type 2 diabetes mellitus
Company Name: SmithKline Beecham Pharmaceuticals
Availability: Prescription only
Approved by FDA: 25 May 1999

Introduction

Despite a growing understanding of the pathophysiology of diabetes mellitus, the long-term management of the disease remains one of the greatest challenges for clinicians. As the number of persons in the US with Type 2 diabetes continues to grow, so does the search for novel, effective and well tolerated therapies. Among the newest forms of therapies are drugs that sensitize the insulin receptor to the action of insulin. The first drug in this class approved in the US was Rezulin (troglitazone). Despite its widespread use and generally good tolerability profile, concerns have been raised about the effect of Rezulin on the liver. Now, Avandia (rosiglitazone) promises to provide good effectiveness while improving on the safety profile of this class of drugs.

How It Works

Insulin exerts its effects by linking to a cellular receptor. Following this interaction, the metabolism of glucose is altered in the cell. Evidence indicates that persons with Type 2 diabetes (formerly known as noninsulin-dependent diabetes) have a defect in their cells that results in reduced responsiveness to insulin. As a class, the thiazolidinediones (also called the “glitazones”) act by “sensitizing” receptors, known as PPAR-gamma receptors, to the effects of insulin. Consequently, the depressed levels of insulin found in persons with Type 2 diabetes achieve a near-normal physiologic effect. Patients who have responded poorly to other traditional oral diabetes therapies, and who have not reached the point where they require insulin injections, appear to respond favorably to Avandia.

Clinical Study Results

Rosiglitazone is one of the most potent members of the thiazolidinediones. Several studies have demonstrated the effectiveness of the drug in persons with diabetes. In one study, 380 diabetics received 12 weeks of treatment with doses ranging from 0.1 mg to 4 mg (given as a twice daily dose). The drug significantly lowered blood glucose compared to placebo, without an accompanying rise in fasting insulin. One fourth of patients receiving the highest dose had complete normalization of their fasting glucose level. The magnitude of effect was considered to be similar to that observed with an 800 mg daily dose of troglitazone. Similar results were observed in a second study of 493 patients.

Some evidence suggests that Avandia’s activity is enhanced when it is given concomitantly with another oral diabetes drug, metformin. Also, Avandia may be slightly more effective in women than in men, although the reasons for this are unclear.

What The Patient Should Know

All antidiabetic drugs, including Avandia, have the potential to cause low blood sugar levels. The dose must be carefully adjusted to ensure adequate control of blood sugar levels but without the development of hypoglycemia.

Because of the development of severe liver damage in some patients who had been treated with troglitazone, the liver safety profile of Avandia remains a concern. However, there has been no indication of hepatotoxicity in controlled clinical trials with Avandia. Nevertheless, it is recognized that hepatic adverse events occur in a very small minority of patients, and that if these adverse events occur with Avandia, they will not be seen until the drug is used by hundreds of thousands of patients.

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.”