Rosiglitazone Maleate

Pronunciation: ROE-si-GLI-ta-zone MAL-ee-ate
Class: Thiazolidinedione

Trade Names

Avandia
- Tablets, oral 2 mg
- Tablets, oral 4 mg
- Tablets, oral 8 mg

Pharmacology

Increases insulin sensitivity in liver, muscle, and adipose tissue.

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Pharmacokinetics

Absorption

Bioavailability is 99%. T max is 1 h. When administered with food, C max is lowered by 28%, with a delay in T max by 1.75 h.

Distribution

Vd is approximately 17.6 L. Protein binding is 99.8%, primarily to albumin.

Metabolism

Extensively metabolized by isoenzyme CYP2C8, with CYP2C9 as a minor pathway.

Elimination

Eliminated in urine (64%) and feces (23%). Plasma half-life is 103 to 158 h. Elimination half-life is 3 to 4 h.

Special Populations

Renal Function Impairment

There are no clinically relevant differences in the pharmacokinetics of rosiglitazone in patients with mild to severe renal impairment or in hemodialysis-dependent patients.

Hepatic Function Impairment

In moderate to severe liver disease (Child-Pugh class B or C), unbound oral Cl was significantly lower, C max and AUC were increased 2- and 3-fold, respectively, and elimination half-life was approximately 2 h longer.

Elderly

Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of rosiglitazone.

Children

Pharmacokinetic parameters studied in children were consistent with parameter estimates in adult patients.

Gender

Mean oral Cl in women was approximately 6% lower.

Race

Race does not affect pharmacokinetics.

Body weight

Oral Cl and oral steady-state Vd were shown to increase with increases in body weight.

Indications and Usage

Improved glycemic control of type 2 diabetes mellitus as monotherapy and as an adjunct to diet and exercise in patients who are already taking rosiglitazone, or are not already taking rosiglitazone but are unable to achieve adequate glycemic control on other diabetes medications, and in consultation with their health care provider, have decided not to take pioglitazone for medical reasons.

Unlabeled Uses

Increased ovulation frequency in women with polycystic ovary syndrome; reduced in-stent restenosis in patients with diabetes.

Contraindications

Initiation in patients with established New York Heart Association (NYHA) class III or IV heart failure.

Dosage and Administration

Type 2 Diabetes
Adults

PO Initiate therapy at 4 mg/day, as a single dose or 2 divided doses. For patients who respond inadequately following 8 to 12 wk of treatment, the dosage may be increased to 8 mg daily (max, 8 mg/day).

Renal Function Impairment
Adults

PO Because metformin is contraindicated in patients with renal impairment, coadministration of metformin and rosiglitazone is also contraindicated in these patients.

Hepatic Function Impairment
Adults

PO Treatment should not be initiated in patients exhibiting evidence of active liver disease or increased serum transaminase levels (ALT more than 2.5 × ULN at the start of therapy).

General Advice

  • Administer without regard to meals. Administer with food if GI upset occurs.
  • Patients receiving rosiglitazone in combination with other hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of concomitant agent may be necessary.
  • Increases in the dose should be accompanied by careful monitoring for adverse reactions related to fluid retention.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

CYP2C8 inducers (eg, rifampin)

May decrease rosiglitazone AUC; changes in diabetes treatment may be needed when the CYP2C8 inducer is started or stopped. Clinical and laboratory monitoring is warranted. Adjust the rosiglitazone dose as needed.

CYP2C8 inhibitors (eg, azole antifungal agents [eg, ketoconazole], fluvoxamine, gemfibrozil, trimethoprim)

May elevate rosiglitazone plasma levels, increasing the pharmacologic effects and adverse reactions. Clinical and laboratory monitoring is warranted. Adjust the rosiglitazone dose as needed.

Insulin

Risk of edema may be increased, even after several months of therapy. Increased risk of CHF and MI. Coadministration is not recommended.

Glyburide

Repeat doses of rosiglitazone may decrease glyburide AUC and C max . Clinical and laboratory monitoring is warranted. Adjust the glyburide dose as needed.

Nevirapine

Rosiglitazone may reduce nevirapine plasma concentrations. Clinical and laboratory monitoring is warranted. Adjust the nevirapine dose as needed.

Adverse Reactions

Cardiovascular

Hypertension; CHF (postmarketing).

CNS

Headache (17%); fatigue (4%).

Dermatologic

Pruritus, rash, Stevens-Johnson syndrome, urticaria (postmarketing)

EENT

Nasopharyngitis, sinusitis (3%); macular edema (postmarketing).

GI

Nausea (4%); diarrhea (2%).

Hematologic-Lymphatic

Anemia (2%); decreased WBC, dose-related decreases in Hgb and Hct.

Hepatic

Hepatic enzyme elevation 3 or more × ULN, hepatic failure, hepatitis (postmarketing).

Lab Tests

Decrease in free fatty acids; increase in HDL, LDL, and total cholesterol.

Metabolic-Nutritional

Hyperglycemia (4%); hypoglycemia (1%); weight gain.

Musculoskeletal

Bone fractures (9%); back pain (4%); arthralgia.

Respiratory

Upper respiratory tract infection (10%); pleural effusion, pulmonary edema (postmarketing).

Miscellaneous

Injury (8%); edema (5%); anaphylactic reactions, angioedema (postmarketing).

Precautions

Warnings

Thiazolidinediones, including rosiglitazone, cause or exacerbate CHF in some patients. After initiation of rosiglitazone and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, manage the heart failure according to current standards of care. Furthermore, consider discontinuation or dose reduction of rosiglitazone.

Rosiglitazone is not recommended in patients with symptomatic heart failure. Initiation of rosiglitazone in patients with established NYHA class III or IV heart failure is contraindicated.

A meta-analysis of 52 clinical trials (mean duration, 6 months; 16,995 total patients), most of which compared rosiglitazone with placebo, showed rosiglitazone to be associated with a statistically significant increased risk of MI.


Monitor

Monitor for signs and symptoms of heart failure. Obtain periodic fasting blood glucose and HbA 1c concentrations to monitor therapeutic response. Assess liver enzymes prior to initiation of therapy and periodically thereafter.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy have not been established.

Hepatic Function

Do not initiate therapy in patients with clinical evidence of active liver disease or baseline ALT more than 2.5 × ULN.

Bone fractures

Increased incidence of bone fractures noted in women; this risk may also apply to men.

Diabetic ketoacidosis

Not recommended.

Edema

Use with caution; can cause fluid retention.

Hematologic

Decreases in Hgb (1 g/dL or less) and Hct (3.3% or less) have been reported; may be related to dose-related increases in plasma volume associated with rosiglitazone therapy.

Hypoglycemia

May increase risk of hypoglycemia when used in combination with other hypoglycemic agents; may need dose reduction of concomitant agent.

Macular edema

Has been reported in postmarketing experience.

Ovulation

May result in resumption of ovulation in premenopausal anovulatory women.

Type 1 diabetes

Not recommended.

Weight gain

Dose-related weight gain has been seen alone and in combination with other hypoglycemic agents. Unusually rapid increases in weight may be caused by fluid accumulation; assess such patients for fluid accumulation and volume-related events.

Overdosage

Symptoms

Limited data are available.

Patient Information

  • Inform patients that rosiglitazone is not recommended for patients with symptomatic heart failure.
  • Inform patients that results of a set of clinical studies suggest that treatment is associated with an increased risk for MI, especially in patients taking insulin.
  • Inform patients that rosiglitazone is not recommended for patients who are taking insulin.
  • Inform patients that management of type 2 diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type 2 diabetes, but in maintaining the efficacy of drug therapy.
  • Inform patients that it is important to adhere to dietary instructions and to regularly have blood glucose and HbA 1c tested. It can take 2 wk to see a reduction in blood glucose and 2 to 3 mo to see the full effect of rosiglitazone.
  • Inform patients that blood will be drawn to check liver function prior to the start of therapy and periodically thereafter per the clinical judgement of their health care provider. Advise patients with unexplained symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine to immediately report these symptoms to their health care provider.
  • Inform patients that if they experience an unusually rapid increase in weight or edema or develop shortness of breath or other symptoms of heart failure while on rosiglitazone, they should immediately report these symptoms to their health care provider.
  • Inform patients that rosiglitazone can be taken with or without meals.
  • Explain the risk of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development to patients and their family members when rosiglitazone is used in combination with other hypoglycemic agents.
  • Inform patients that therapy with rosiglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking rosiglitazone. Thus, recommend adequate contraception in premenopausal women.

Copyright © 2009 Wolters Kluwer Health.

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