Rosiglitazone
From Pubdrug
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This drug has a Black Box warning from the U.S. Food and Drug Administration. |
Authored by: Mleong  | ||||
| Rosiglitazone general drug information | ||||
| Pronunciation | roh si GLI ta zone (.wav file) | |||
| Trade Name(s) | Avandia | |||
| How Supplied | Tablets: 2 mg, 4 mg, 8 mg | |||
| Generic Availability | No generics available | |||
| Patent Expiry Date | August 11, 2017 | |||
| Classification | Antidiabetic agent, Thiazolidinedione | |||
| Schedule | Rx | |||
| Pregnancy Category | C | |||
| Breast-feeding | Excretion in breast milk unknown. Use is not recommended while breastfeeding. | |||
| Rosiglitazone chemical information | ||||
| IUPAC Name | 5-((4-(2-(methyl-2-pyridinylamino) ethoxy)phenyl)methyl)- 2,4-thiazolidinedione | |||
| Empirical Formula | C18H19N3O3S•C4H4O4 | |||
| Molecular Weight | 357.428 g/mol | |||
| pharmacokinetic information | pharmacogenomic information | ||||
Description
Rosiglitazone belongs to a class of medications known as Thiazolidinedione.[1] It is an oral antidiabetic agent used in the treatment of Type 2 diabetes mellitus (noninsulin dependent, NIDDM). Blood glucose lowering effects come from its ability to increase insulin sensitivity.[2]
Mechanism of Action
Rosiglitazone improves glycemic control by increasing insulin sensitivity in liver, muscle, and adipose tissues and inhibits hepatic gluconeogenesis. It is also a highly selective and potent agonist for the peroxisome proliferator-actived receptor (PPAR). These receptors are found in humans in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. They control a number of gene products involved in glucose and lipid metabolism.[1][2]
Time Required for Therapeutic Response
Pharmacokinetics
Absorption
The absolute bioavailability of rosiglitazone is approximately 99%, with plasma concentrations peaking about 1 hour after dosing. Coadministration with food has no effect on AUC, but there is a 28% decrease in Cmax and a 1.75 hour delay in Tmax.[2][3]
Distribution
Approximately 99.8% of the circulating drug is plasma protein bound, primarily to albumin. The volume of distribution is approximately 17.6 L.[2][3]
Metabolism
The parent drug is extensively metabolized by N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. In vitro data show that rosiglitazone is a substrate of the CYP 2C8 isoenzyme, with CYP 2C9 contributing as a minor pathway. All of the circulating metabolites excreted into the urine are less potent than the parent therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone.[2][3]
Excretion
Approximately 64% of a rosiglitazone dose is eliminated in urine, while 23% is eliminated in the feces. The half-life of elimination is 3-7 hours.[2][3]
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Special Population Pharmacokinetics
- Renal insufficiency: No dose adjustment is needed.[2]
- Hepatic insufficiency: Clinical studies show that, compared to healthy subjects, patients with moderate to severe liver disease experienced a significantly lower oral clearance, increased Cmax and AUC (by 2 and 3 fold, respectively) and increased elimination half (about 2 hours longer). Therapy should not be initiated in patients with active liver disease or increased serum transaminase (ALT>2.5 times the upper limit of normal).[2]
- Hemodialysis: No dose adjustment is needed.[2]
- Geriatric: No dose adjustment is needed.[2]
- Pediatric: Clearance and bioavailability values are similar to those seen in adults, but the manufacturer does not recommend rosiglitazone use for pediatric patients.[2]
- Gender: Mean oral clearance of rosiglitazone in female patients was approximately 6% lower versus male patients of the same body weight. In combination therapy with metformin, there was no difference in efficacy with respect to gender. The molecular target PPARγ is expressed in adipose tissues - therefore, a greater therapeutic response may be observed in females because they tend to have a higher percentage of body fat versus males. Still, the manufacturer recommends that no dose adjustments be made solely on the basis of gender - rather, the dose should be individualized based on patient response.[2]
Indications and Dosages
FDA Approved Indications
Treatment of type 2 diabetes mellitus (as monotherapy, or in combination with a sulfonylurea, metformin, a sulfonylurea plus metformin, or insulin)
- Starting dose (adults):
- 4mg as a single daily dose or two divided doses
- Maintenance dose (adults):
- After 12 weeks, if response is inadequate the dose may be increased to 8 mg daily, given as a single dose or in two divided doses[2]
- Titration schedule (adults): For patients with an inadequate reduction in blood glucose after 8 to 12 weeks of treatment, the dose may be increased to 8 mg daily
Non-FDA Approved Indications
- Polycystic Ovary Syndrome (PCOS)[4]
Dosage Adjustment
Renal insufficiency: No dose adjustment required.
Hepatic insufficiency: Rosiglitazone should not be started in patients who have clinical evidence of active liver disease or increased serum transaminase levels (ALT>2.5 times the upper limit of normal) at start of therapy. Liver enzyme monitoring is recommended in all patients prior to initiation of therapy and periodically thereafter.
Hemodialysis: No dose adjustment required.[5]
Geriatric: No dose adjustment required.
Pediatric: Due to a lack of data, the manufacturer does not recommend pediatric use of rosiglitazone.
Gender: No dose adjustment required.[1]
Dosage Limits
- Adults: 8mg daily[2]
- Elderly: 8mg daily[2]
- Doses of rosiglitazone greater than 4mg daily in combination with insulin are not recommended.[2]
- Adolescents and children: Due to a lack of data, the manufacturer does not recommend pediatric use of rosiglitazone.[2]
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Administration
- Route: Oral
- Method:
- Take with a full glass of water.
- Tablet can be taken at any time during the day, but at the same time each day.
- May be taken with or without food.[6]
Monitoring Parameters
- Hemoglobin A1C
- Blood glucose
- Signs and symptoms of heart failure
- Liver enzymes (prior to initiation of therapy, then periodically thereafter).[2]
- If ALT levels are elevated to >3X upper limit of normal rosiglitazone therapy should be discontinued.[2]
Contraindications/Precautions
Black box warning
Thiazolidinediones have been shown to cause or exacerbate congestive heart failure. These drugs should not be started in patients with NYHA Class III or IV heart failure. Additionally, patients currently receiving thiazolidinediones should be monitored for signs or symptoms of heart failure - if this disease manifests itself, it may be necessary to discontinue the drug.[2]
Contraindications
- Hypersensitivity to rosiglitazone or any of its components
- Hepatic disease (transaminases >2.5 times the upper limit of normal at baseline)
- Type 1 Diabetes
- Ketoacidosis
- NYHA Class III or IV heart failure.[2]
Precautions
- Caution should be used in females because an increased incidence of bone fracture has been observed in female patients taking Avandia in a long-term trial.[7]
- Caution should be exercised in evaluating weight gain to make sure it is not edema and/or signs and symptoms of heart failure.
- Rosiglitazone therapy may result in ovulation in some premenopausal anovulatory women therefore these patients may be at an increased risk for pregnancy while taking rosiglitazone. Adequate contraception in premenopausal women should be recommended.[6]
- Caution should be exercised when initiating rosiglitazone therapy in those with hepatic disease.
- Use with caution in patients with a pre-existing macular edema or diabetic retinopathy.
Pregnancy indications
Category C
Treatment studies in animal models done during mid to late gestation was associated with fetal death and growth retardation. Abnormal glucose levels are associated with a higher incidence of congenital abnormalities. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy. Rosiglitazone may be used during pregnancy only if the potential benefits justify the potential risks to the fetus.
Breast-feeding indications
Excretion in breast milk is unknown and use of rosiglitazone is not recommended by manufacturer.
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Drug-Drug, -Food, -Herb Interactions
Click the link above to go to the drug interactions page.
Adverse Reactions/Side Effects
| Incidence | Endocrine & metabolic | Adverse Reactions |
| >10% | Endocrine & Metabolic | Weight gain (54%), increase in total cholesterol, increased LDL-cholesterol, increased HDL-cholesterol |
| 1-10% | CNS | Headache (6%), fatigue (4%) |
| Cardiovascular | Edema (5%) | |
| Hematologic | Anemia (2%) | |
| Gastrointestinal | Diarrhea (2%) | |
| Endocrine & metabolic | Hyperglycemia (4%), hypoglycemia (1%; increased with insulin to 12% to 14%) | |
| Neuromuscular/skeletal | Back pain (4%) | |
| Respiratory | Upper respiratory tract infection (10%), sinusitis (3%) | |
| Miscellaneous | Injury(8%) | |
| <1% | All | Angioedema, CHF or exacerbation of CHF, trasaminases increased, hepatic failure, hepatitis, bilirubin increased, macular edema, pleural effusion, pulmonary edema, urticaria, weight gain |
Overdosage Measures
Overdose may manifest as a hypoglycemia.
Treatment:
- Limited data are available with regard to overdosage in humans.
- In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status.
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Product Information and Distribution
| Dose/form | Drug color(s) | Drug shape | Markings or odor/flavor |
| 2 mg tablet | pink | pentagon | 2/SB |
| 4 mg tablet | orange | pentagon | 4/SB |
| 8 mg tablet | red-brown | pentagon | 8/SB |
- Inactive ingredients for tablets: Hypromellose 2910, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch glycolate, titanium dioxide, triacetin, and 1 or more of the following: Synthetic red and yellow iron oxides and talc.
Patient Information
- Take as directed by physician with a glass of water.
- May be taken with or without food.
- If a dose is missed, take as soon as you remember, unless it is time for next dose. Take next dose at the usual time. Do not take a double dose to make up for a missed dose.
- Test blood sugar regularly as directed by physician.
- Diet, weight loss and exercise can help with diabetes.
- It can take 2 weeks for the medication to work. It may take 2 to 3 months to see the full effect on your blood sugar level.
- Physician should check A1C for adequate glucose control and eyes for vision changes regularly at office visits.
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References
- ↑ 1.0 1.1 1.2 Lexi-Comp (2006-07). Drug Information Handbook. 14th Edition., APhA.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 Avandia®(Rosiglitazone maleate) package insert,Research Triangle Park, NC; GlaxoSmithKline:2007 http://us.gsk.com/products/assets/us_avandia.pdf
- ↑ 3.0 3.1 3.2 3.3 Cox PJ, Ryan DA, Hollis FJ, Harris AM, Miller AK, Vousden M, Cowley H. Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans. Drug Metab Dispos. 2000 Jul;28(7):772-80
- ↑ Pillai A, Bang H, Green C. Metformin and glitazones: do they really help PCOS patients? J Fam Pract. 2007 Jun;56(6):444-53
- ↑ Thompson-Culkin K, Zussman B, Miller AK, Freed MI. Pharmacokinetics of rosiglitazone in patients with end-stage renal disease. J Int Med Res. 2002 Jul-Aug;30(4):391-9.
- ↑ 6.0 6.1 Avandia (Rosiglitazone) Avandia®(Rosiglitazone maleate) Patient Information,Research Triangle Park, NC; GlaxoSmithKline:2007 http://www.avandia.com/avandia_medicine.html
- ↑ Berberoglu Z, Gursoy A, Bayraktar N, Yazici AC, Tutuncu NB, Demirag NG. Rosiglitazone Decreases Serum Bone-Specific Alkaline Phosphatase Activity in Postmenopausal Diabetic Women. J Clin Endocrinol Metab. 2007 Jun 26
PUBMED References
Efficacy Trial Articles
- Dargie HJ, Hildebrandt PR, Riegger GA, McMurray JJ, McMorn SO, Roberts JN, Zambanini A, Wilding JP. A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association Functional Class I or II Heart Failure. J Am Coll Cardiol. 2007 Apr 24;49(16):1696-704. Epub 2007 Apr 6
- Weissman P, Goldstein BJ, Rosenstock J, Waterhouse B, Cobitz AR, Wooddell MJ, Strow LJ. Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study. Curr Med Res Opin. 2005 Dec;21(12):2029-35
- Shargorodsky M, Wainstein J, Gavish D, Leibovitz E, Matas Z, Zimlichman R. Treatment with rosiglitazone reduces hyperinsulinemia and improves arterial elasticity in patients with type 2 diabetes mellitus. Am J Hypertens. 2003 Aug;16(8):617-22
- Scheen AJ. ADOPT study: which first-line glucose-lowering oral medication in type 2 diabetes? Rev Med Liege. 2007 Jan;62(1):48-52
- Garg R, Gopal J, Jones GR. Rosiglitazone: safety and efficacy in combination with insulin in poorly controlled type 2 diabetes mellitus patients treated with insulin alone. J Diabetes Complications. 2007 Jan-Feb;21(1):1-6.
- Rosak C, Standl E, Reblin T, Stammer H, Seidel DK. Rosiglitazone is effective and well-tolerated in a range of therapeutic regimens during daily practice in patients with type 2 diabetes. Int J Clin Pract. 2006 Sep;60(9):1040-7
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Therapeutic Class Comparison Articles
- Ko GT, Tsang PC, Wai HP, Kan EC, Chan HC. Rosiglitazone versus bedtime insulin in the treatment of patients with conventional oral antidiabetic drug failure: a 1-year randomized clinical trial. Adv Ther. 2006 Sep-Oct;23(5):799-808
- Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006 Dec 7;355(23):2427-43. Epub 2006 Dec 4
Pharmacokinetics Articles
- Kirchheiner J, Thomas S, Bauer S, Tomalik-Scharte D, Hering U, Doroshyenko O, Jetter A, Stehle S, Tsahuridu M, Meineke I, Brockmöller J, Fuhr U. Pharmacokinetics and pharmacodynamics of rosiglitazone in relation to CYP2C8 genotype. Clin Pharmacol Ther. 2006 Dec;80(6):657-67
- Chapelsky MC, Thompson-Culkin K, Miller AK, Sack M, Blum R, Freed MI. Pharmacokinetics of rosiglitazone in patients with varying degrees of renal insufficiency. J Clin Pharmacol. 2003 Mar;43(3):252-9
- Virtanen KA, Hällsten K, Parkkola R, Janatuinen T, Lönnqvist F, Viljanen T, Rönnemaa T, Knuuti J, Huupponen R, Lönnroth P, Nuutila P. Differential effects of rosiglitazone and metformin on adipose tissue distribution and glucose uptake in type 2 diabetic subjects. Diabetes. 2003 Feb;52(2):283-90
- Thompson-Culkin K, Zussman B, Miller AK, Freed MI. Pharmacokinetics of rosiglitazone in patients with end-stage renal disease. J Int Med Res. 2002 Jul-Aug;30(4):391-9
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Drug Interaction Articles
- Kim KA, Park PW, Kim KR, Park JY. Effect of multiple doses of montelukast on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans. Br J Clin Pharmacol. 2007 Mar;63(3):339-45. Epub 2006 Sep 19
- Park JY, Kim KA, Shin JG, Lee KY. Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects. Br J Clin Pharmacol. 2004 Oct;58(4):397-402
Adverse Effects Articles
- Cekmen N, Cesur M, Cetinbas R, Bedel P, Erdemli O. Acute pulmonary edema due to rosiglitazone use in a patient with diabetes mellitus. J Intensive Care Med. 2006 Jan-Feb;21(1):47-50
- Liu X, Huang T, Sahud MA. Rosiglitazone-induced immune thrombocytopenia. Platelets. 2006 May;17(3):143-8
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Compliance Articles
Pharmacoeconomic Articles
- Shearer AT, Bagust A, Liebl A, Schoeffski O, Goertz A. Cost-effectiveness of rosiglitazone oral combination for the treatment of type 2 diabetes in Germany. Pharmacoeconomics. 2006;24 Suppl 1:35-48
- Shearer AT, Bagust A, Ampudia-Blasco FJ, Martínez-Lage Alvarez B, Pérez Escolano I, París G. Lifetime health consequences and cost-effectiveness of rosiglitazone in combination with metformin for the treatment of type 2 diabetes in Spain. Pharmacoeconomics. 2006;24 Suppl 1:49-59
- Beale S, Bagust A, Shearer AT, Martin A, Hulme L. Cost-effectiveness of rosiglitazone combination therapy for the treatment of type 2 diabetes mellitus in the UK. Pharmacoeconomics. 2006;24 Suppl 1:21-34
- Kalsekar I, Iyer S, Mody R, Rajagopalan R, Kavookjian J. Utilization and costs for compliant patients initiating therapy with pioglitazone or rosiglitazone versus insulin in a Medicaid fee-for-service population. J Manag Care Pharm. 2006 Mar;12(2):121-9
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External Links
Clinical treatment guidelines
Patient information pages
Other resources
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