Rosiglitazone Maleate

(BANM, USAN, rINNM)
Rosiglitazone Maleate Chemical formula
Synonyms: (BANM, USAN, rINNM) BRL-49653-C; Maleato de rosiglitazona; Rosiglitazone, Maléate de; Rosiglitazoni Maleas; Roziglitazon Maleat. (±)-5-{p-[2-(Methyl-2-pyridylamino)ethoxy]benzyl}-2,4-thiazolidinedione maleate (1:1).
Cyrillic synonym: Розиглитазона Малеат.

💊 Chemical information

Chemical formula: C18H19N3O3S,C4H4O4 = 473.5.
CAS — 122320-73-4 (rosiglitazone); 155141-29-0 (rosiglitazone maleate); 316371-84-3 (rosiglitazone potassium).
ATC — A10BG02.
ATC Vet — QA10BG02.

💊 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 hypercholesterolaemia. 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 study1 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;2 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 in creased fracture risk with rosiglitazone,2 and data from the manufacturer of pioglitazone involving over 8100 treated patients also revealed an increased risk of fracture in women given the drug;3 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.4
1. Kahn SE, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427–43. Correction. ibid. 2007; 356: 1387–8
2. GSK, Canada. Increased incidence of fractures in female patients who received long-term treatment with Avandia (rosiglitazone maleate) tablets for type 2 diabetes mellitus (23rd February 2007). Available at: http://www.hc-sc.gc.ca/dhp-mps/ alt_formats/hpfb-dgpsa/pdf/medeff/avandia_hpc-cps_3-eng.pdf (accessed 20/08/08
3. Takeda, USA. Re observation of an increased incidence of fractures in female patients who received long-term treatment with Actos (pioglitazone HCl) tablets for type 2 diabetes mellitus (March 2007). Available at: http://www.fda.gov/medwatch/ safety/2007/Actosmar0807.pdf (accessed 21/03/07
4. Schwartz AV, et al. Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab 2006; 91: 3349–54.

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. However, a meta-analysis1 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-analysis2 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,1 and this has been questioned. An alternative analysis3 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).4 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.
1. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 2457–71. Correction. ibid.; 357: 100
2. Singh S, et al. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007; 298: 1189–95
3. Diamond GA, et al. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med 2007; 147: 578–81
4. Home PD, et al. RECORD Study Group. Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis. N Engl J Med 2007; 357: 28–38.

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.1,2 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.2
1. GSK, USA. Avandia (rosiglitazone maleate), Avandamet (rosiglitazone maleate/metformin HCl): letter to healthcare professionals (issued December 2005). Available at: http://www.fda.gov/medwaTCH/safety/2006/ Avandia_DHCPletter.pdf (accessed 03/05/06
2. GSK, Canada. Association of Avandia and Avandamet with new onset and/or worsening of macular edema (issued 19th December, 2005). Available at: http://www.hc-sc.gc.ca/dhp-mps/ alt_formats/hpfb-dgpsa/pdf/medeff/avandia_avandamet_ hpc-cps-eng.pdf (accessed 20/08/08)

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.1-6 A large retrospective cohort study7 also found that the use of thiazolidinediones increased the risk of heart failure. The incidence of peripheral oedema with monotherapy has been reported8 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,9 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.10 The American Heart Association and American Diabetes Association have recommended8 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.
1. Page RL, et al. Possible heart failure exacerbation associated with rosiglitazone: case report and literature review. Pharmacotherapy 2003; 23: 945–54
2. Kermani A, Garg A. Thiazolidinedione-associated congestive heart failure and pulmonary edema. Mayo Clin Proc 2003; 78: 1088–91
3. Bell DSH. Unilateral edema due to a thiazolidinedione. Diabetes Care 2003; 26: 2700
4. Shah M, et al. Pioglitazone-induced heart failure despite normal left ventricular function. Am J Med 2004; 117: 973–4
5. CSM/MHRA. Reminder: thiazolidinediones (glitazones) contraindications. Current Problems 2004; 30: 8. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_ FILE&dDocName=CON007448&RevisionSelectionMethod= LatestReleased (accessed 02/06/06
6. Cheng AYY, Fantus IG. Thiazolidinedione-induced congestive heart failure. Ann Pharmacother 2004; 38: 817–20
7. Delea TE, et al. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study. Diabetes Care 2003; 26: 2983–9
8. Nesto RW, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Circulation 2003; 108: 2941–8. Also available at: http:// circ.ahajournals.org/cgi/reprint/108/23/2941.pdf (accessed 26/03/07) Also published in Diabetes Care 2004; 27: 256–63. Also available at: http://care.diabetesjournals.org/cgi/reprint/ 27/1/256 (accessed 26/03/07
9. Dormandy JA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366: 1279–89
10. Rydén L, et al. Adjudication of serious heart failure in patients from PROactive. Lancet 2007; 369: 189–90.

Effects on lipids.

Effects on the liver.

Several cases of hepatotoxicity have been described1-5 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 debated6,7 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 ALT 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.
1. Forman LM, et al. Hepatic failure in a patient taking rosiglitazone. Ann Intern Med 2000; 132: 118–21
2. Al-Salman J, et al. Hepatocellular injury in a patient receiving rosiglitazone: a case report. Ann Intern Med 2000; 132: 121–4
3. Ravinuthala RS, Nori U. Rosiglitazone toxicity. Ann Intern Med 2000; 133: 658
4. Hachey DM, et al. Isolated elevation of alkaline phosphatase level associated with rosiglitazone. Ann Intern Med 2000; 133: 752
5. Gouda HE, et al. Liver failure in a patient treated with long-term rosiglitazone therapy. Am J Med 2001; 111: 584–5
6. Freid J, et al. Rosiglitazone and hepatic failure. Ann Intern Med 2000; 132: 164
7. Isley WL, Oki JC. Rosiglitazone and liver failure. Ann Intern Med 2000; 133: 393.

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 studies1,2 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.2,3
1. Park J-Y, et al. Effect of rifampin on the pharmacokinetics of rosiglitazone in healthy subjects. Clin Pharmacol Ther 2004; 75: 157–62
2. Niemi M, et al. Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone. Clin Pharmacol Ther 2004; 76: 239–49
3. Hruska MW, et al. The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects. Br J Clin Pharmacol 2005; 59: 70–9.

Antifungals.

In a study1 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.
1. Park J-Y, et al. Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects. Br J Clin Pharmacol 2004; 58: 397–402.

Lipid regulating drugs.

Gemfibrozil increased the plasma concentration and about doubled the half-life of rosiglitazone in a study1 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.
1. Niemi M, et al. Gemfibrozil considerably increases the plasma concentrations of rosiglitazone. Diabetologia 2003; 46: 1319–23.

💊 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.
1. Baldwin SJ, et al. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol 1999; 48: 424–32
2. Chapelsky MC, et al. Pharmacokinetics of rosiglitazone in patients with varying degrees of renal insufficiency. J Clin Pharmacol 2003; 43: 252–9.

💊 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.
1. Nolan JJ, et al. Rosiglitazone taken once daily provides effective glycaemic control in patients with type 2 diabetes mellitus. Diabet Med 2000; 17: 287–94
2. Fonseca V, et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 2000; 283: 1695–1702. Correction. ibid.; 284: 1384
3. Lebovitz HE, et al. Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 2001; 86: 280–8
4. Anonymous. Pioglitazone and rosiglitazone for diabetes. Drug Ther Bull 2001; 39: 65–8
5. Parulkar AA, et al. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med 2001; 134: 61–71
6. Raskin P, et al. A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care 2001; 24: 1226–32
7. O’Moore-Sullivan TM, Prins JB. Thiazolidinediones and type 2 diabetes: new drugs for an old disease. Med J Aust 2002; 176: 381–6. Correction. ibid.; 177: 396.
8. Wagstaff AJ, Goa KL. Rosiglitazone: a review of its use in the management of type 2 diabetes mellitus. Drugs 2002; 62: 1805–37
9. Diamant M, Heine RJ. Thiazolidinediones in type 2 diabetes mellitus: current clinical evidence. Drugs 2003; 63: 1373–1405
10. Yki-Järvinen H. Thiazolidinediones. N Engl J Med 2004; 351: 1106–18
11. Dailey GE, et al. Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial. Am J Med 2004; 116: 223–9
12. Czoski-Murray C, et al. Clinical effectiveness and cost-effectiveness of pioglitazone and rosiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation. Health Technol Assess 2004; 8: 1–91
13. Wellington K. Rosiglitazone/metformin. Drugs 2005; 65: 1581–92
14. Deeks ED, Keam SJ. Rosiglitazone : a review of its use in type 2 diabetes mellitus. Drugs 2007; 67: 2747–79.

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.1 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 contraindicate 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.
1. NICE. Guidance on the use of glitazones for the treatment of type 2 diabetes (issued August 2003). Available at: http:// www.nice.org.uk/pdf/TA63_Glitazones_Review_Guidance.pdf (accessed 17/03/05)

Inflammatory bowel disease.

There is some evidence1 to suggest that drugs such as rosiglitazone that act as ligands to peroxisome proliferator-activated receptor γ (PPARγ) may offer a novel therapeutic approach to management of inflammatory bowel disease.
1. Lewis JD, et al. Rosiglitazone for Ulcerative Colitis Study Group. Rosiglitazone for active ulcerative colitis: a randomized placebo-controlled trial. Gastroenterology 2008; 134: 688–95.
Polycystic ovary syndrome . Insulin resistance is a feature of polycystic ovary syndrome and the use of rosiglitazone is under investigation.1-3
1. Baillargeon J-P, et al. Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil Steril 2004; 82: 893–902
2. Dereli D, et al. Endocrine and metabolic effects of rosiglitazone in non-obese women with polycystic ovary disease. Endocr J 2005; 52: 299–308
3. Yilmaz M, et al. The effects of rosiglitazone and metformin on menstrual cyclicity and hirsutism in polycystic ovary syndrome. Gynecol Endocrinol 2005; 21: 154–60.

💊 Preparations

Proprietary Preparations

Arg.: Avandia; Diaben; Gaudil; Glimide; Gliximina; Gludex; Rosiglit; Austral.: Avandia; Belg.: Avandia; Braz.: Avandia; Canad.: Avandia; Chile: Avandia; Cz.: Avandia; Denm.: Avandia; Fin.: Avandia; Fr.: Avandia; Ger.: Avandia; Gr.: Avandia; Hong Kong: Avandia; Hung.: Avandia; India: Rezult†; Roglin; Rosicon; Indon.: Avandia; Irl.: Avandia; Israel: Avandia; Ital.: Avandia; Malaysia: Avandia; Mex.: Avandia; Neth.: Avandia; Norw.: Avandia; NZ: Avandia; Philipp.: Avandia; Pol.: Avandia; Port.: Avandia; Rus.: Avandia (Авандия); Roglit (Роглит); S.Afr.: Avandia; Singapore: Avandia; Spain: Avandia; Swed.: Avandia; Switz.: Avandia; Thai.: Avandia; Turk.: Avandia; UK: Avandia; USA: Avandia; Venez.: Avandia. Multi-ingredient: Arg.: Avandamet; Gludex Plus; Rosiglit-Met; Austral.: Avandamet; Belg.: Avandamet; Canad.: Avandamet; Chile: Avandamet; Cz.: Avaglim; Avandamet; Denm.: Avandamet; Fin.: Avandamet; Fr.: Avaglim; Avandamet; Ger.: Avandamet; Gr.: Avaglim; Avandamet; Hong Kong: Avandamet; Hung.: Avaglim; Avandamet; India: Glyroz; Roglin-M; Rosicon MF; Indon.: Avandamet; Avandaryl; Irl.: Avandamet; Israel: Avandamet; Ital.: Avandamet; Malaysia: Avandamet; Mex.: Avandamet; Neth.: Avandamet; Norw.: Avandamet; Philipp.: Avandamet; Pol.: Avandamet; Port.: Avaglim; Avandamet; Singapore: Avandamet; Spain: Avandamet; Swed.: Avandamet; Switz.: Avandamet; Thai.: Avandamet; UK: Avandamet; USA: Avandamet; Avandaryl; Venez.: Avandamet.
Published November 27, 2018.