Rosiglitazone Maleate

Class: Thiazolidinediones
VA Class: HS502
Chemical Name: (±)-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]-phenyl]methyl]-2,4-thiazolidinedione, (Z)-2-butenedioate
Molecular Formula: C₁₈H₁₉N₃O₃S•C₄H₄O₄
CAS Number: 122320-73-4
Brands: Avandia, Avandamet, Avandaryl

Special Alerts:

[UPDATED 02/04/2011] FDA notified healthcare professionals and patients that information on the cardiovascular risks (including heart attack) of rosiglitazone has been added to the physician labeling and patient Medication Guide. This information was first announced by FDA on September 23, 2010 as part of new restrictions for prescribing and use of this drug.

Rosiglitazone is sold as a single-ingredient product under the brand name Avandia. Rosiglitazone is also sold as a combination product under the brand name Avandamet (contains rosiglitazone and metformin) and under the brand name Avandaryl (contains rosiglitazone and glimepiride).

In addition to describing the cardiovascular risks, the drug labels have been revised to state that rosiglitazone and rosiglitazone-containing medicines should only be used:

• 
  

  In patients already being treated with these medicines

  
  


• 
  

  In patients whose blood sugar cannot be controlled with other anti-diabetic medicines and who, after consulting with their healthcare professional, do not wish to use pioglitazone-containing medicines (Actos, Actoplus Met, Actoplus Met XR, or Duetact).

  
  

For more information visit the FDA website at: and .

[Posted 09/23/2010] ISSUE: FDA notified healthcare professionals and patients that it will significantly restrict the use of the diabetes drug rosiglitazone (Avandia) to patients with Type 2 diabetes who cannot control their diabetes on other medications. These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with rosiglitazone

BACKGROUND: Rosiglitazone is in a class of drugs known as thiazolidinediones, or TZDs. It is intended to be used in conjunction with diet and exercise to improve glucose (blood sugar) control in patients with Type 2 diabetes mellitus. Rosiglitazone also is available in combination with other diabetes medications, metformin under the brand name Avandamet or glimepiride under the brand name Avandaryl.

RECOMMENDATION: FDA will require that GSK develop a restricted access program for rosiglitazone under a risk evaluation and mitigation strategy, or REMS. Under the REMS, rosiglitazone will be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take pioglitazone (Actos), the only other drug in this class. Current users of rosiglitazone who are benefiting from the drug will be able to continue using the medication if they choose to do so.

Doctors will have to attest to and document their patients' eligibility; patients will have to review statements describing the cardiovascular safety concerns associated with this drug and acknowledge they understand the risks. The agency anticipates that the REMS will limit use of rosiglitazone significantly. For more information visit the FDA website at: and .

[Posted 02/22/2010] FDA notified healthcare professional and patients that it is reviewing the primary data from a large, long-term clinical study, RECORD, on possible cardiovascular risks with the diabetes drug, rosiglitazone (Avandia). In addition to the clinical trial, a number of observational studies of the cardiovascular safety of rosiglitazone have been published and FDA has been reviewing these on an ongoing basis.

These reviews are ongoing and no new conclusions or recommendations about the use of rosiglitazone in the treatment of type 2 diabetes have been made at this time. Once FDA completes its review of the data from the RECORD study, the agency will present the totality of new and existing cardiovascular safety data on rosiglitazone at a public meeting in July 2010. The Agency will provide an updated assessment of the risks and benefits of rosiglitazone in the treatment of type 2 diabetes.

FDA recommends that healthcare professionals follow the recommendations in the drug label when prescribing rosiglitazone. This includes a Boxed Warning. Patients should continue taking rosiglitazone unless told by their healthcare professional to stop. Patients who are concerned about the possible risks associated with using rosiglitazone should talk to their healthcare professional. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for rosiglitazone to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of rosiglitazone and consists of the following: medication guide, elements to assure safe use, communication plan, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

• CHF


• 
  

  Thiazolidinediones, including rosiglitazone, cause or exacerbate CHF in some patients.^{1 116 117 128 141 143 c d} Monitor patients for signs and symptoms of CHF (e.g., dyspnea, rapid weight gain, edema) after initiation of therapy and dosage titration.^{1 117 128 c d} If signs and symptoms of CHF develop, manage disorder according to current standards of care; in addition, consider discontinuance or reduction in dosage of rosiglitazone.^{1 117 128 c d}

  
  


• 
  

  Not recommended in patients with symptomatic CHF (NYHA class I or II).^{1 110 113 118 a}

  
  


• 
  

  Initiation of rosiglitazone in patients with NYHA class III or IV CHF contraindicated.^{1 110 118 128} (See Heart Failure and Other Cardiac Effects under Cautions.)

  
  

• Myocardial Ischemia


• 
  

  Potential risk for myocardial ischemia (e.g., angina, MI); available data on such risk inconclusive.^{128 a k} Findings from a meta-analysis of short-term clinical trials (6 months; 42 clinical trials, majority placebo-controlled) indicate the risk of myocardial ischemia is increased in patients receiving rosiglitazone.^{130 134 144 a} Data from 3 large long-term clinical trials that compared rosiglitazone with placebo or active comparators did not confirm or exclude this risk.^{123 126 131 a}

  
  

Introduction

Antidiabetic agent; thiazolidinedione (glitazone).^{1 2 3 4 6 7 9 10 11 13 14 16 20 30}

Uses for Rosiglitazone Maleate

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Treatment of Diabetes Mellitus

Used alone or in combination with a sulfonylurea, metformin, or a sulfonylurea and metformin as an adjunct to diet and exercise for the management of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM).^{30 106 112 118 121 a} Should be added to, not substituted for, sulfonylurea or metformin therapy.¹

May be added to glyburide/metformin hydrochloride fixed-combination therapy if hyperglycemia is not adequately controlled with the fixed combination.^m Used in combination with a sulfonylurea and metformin (given separately) in patients who have inadequate glycemic control with a sulfonylurea and metformin.¹ May be used in combination with repaglinide if hyperglycemia is not adequately controlled with diet, exercise, and monotherapy with metformin, a sulfonylurea, repaglinide, or a thiazolidinedione.¹¹⁵

Use fixed combination of rosiglitazone/metformin hydrochloride (Avandamet) when treatment with rosiglitazone and metformin is appropriate.^c

Use fixed combination of rosiglitazone/glimepiride (Avandaryl) when treatment with rosiglitazone and glimepiride is appropriate.¹¹⁸ Safety and efficacy of switching to the fixed combination of rosiglitazone/glimepiride in patients previously receiving other oral antidiabetic agents not established.¹¹⁸

Metformin is the preferred initial oral antidiabetic agent for patients with type 2 diabetes mellitus.¹²¹ Thiazolidinediones are one of several second-line agents used with other oral antidiabetic agents (e.g., metformin) in patients who are inadequately controlled on their current oral therapy.¹²¹ Because of potential for serious adverse effects (see Boxed Warning), American Diabetes Association (ADA) recommends that clinicians carefully weigh the potential risks and benefits of thiazolidinediones versus other second-line agents (i.e., insulin, sulfonylureas).^{a k}

Use in combination with insulin not recommended.^{a d} (See Heart Failure and Other Cardiac Effects under Cautions and also Specific Drugs under Interactions.)

Use with nitrates not recommended.^a (See Specific Drugs under Interactions.)

Not effective as sole therapy for type 1 diabetes mellitus or diabetic ketoacidosis; insulin is necessary.^{1 c d i}

Prevention of Diabetes Mellitus

Has been used to reduce the progression to frank diabetes mellitus† in patients at high risk for type 2 diabetes mellitus (i.e., those with impaired glucose tolerance or impaired fasting glucose concentrations).^{123 124} Use of rosiglitazone was associated with a lower incidence of diabetes mellitus than use of placebo in one large trial.¹²³ However, CHF occurred more frequently in patients receiving rosiglitazone than in those receiving placebo.¹²³ (See Heart Failure and Other Cardiac Effects under Cautions.)

Rosiglitazone Maleate Dosage and Administration

General

• 
  

  Carefully individualize dosage based on patient's response and tolerance.^{1 110 118}

  
  


• 
  

  Monitor regularly (e.g., fasting blood glucose concentrations, hemoglobin A_1c [HbA_1c]) to determine therapeutic response and minimum effective dosage.^{1 1 110 118 i}

  
  


• 
  

  Allow sufficient time to assess therapeutic response (8–12 weeks) to rosiglitazone.^{1 110 118}

  
  


• 
  

  When initiating therapy, consider the benefit-to-risk ratio of monotherapy versus combination therapy.^{110 118}

  
  

Administration

Oral Administration

Administer rosiglitazone once or twice daily without regard to meals.^{1 25 i}

Administer rosiglitazone/metformin hydrochloride fixed-combination preparation in divided doses with meals.¹¹⁰

Administer rosiglitazone/glimepiride fixed-combination preparation once daily with the first main meal of the day.^{118 h}

If a dose is missed, take the missed dose as soon as it is remembered.^{136 h} If the missed dose is remembered at the time of the next dose, skip missed dose and resume the regular schedule.^{136 h} Do not double dose to replace missed dose.^{136 h}

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as rosiglitazone maleate; dosage expressed in terms of rosiglitazone.¹

Adults

Treatment of Diabetes Mellitus

Monotherapy

Oral

Usual initial dosage is 4 mg daily in 1 or 2 divided doses.^{1 i} If response is inadequate after 8–12 weeks, increase dosage to a maximum of 8 mg daily.¹

Combination Therapy with Other Antidiabetic Agents

Oral

May continue current dosage of the sulfonylurea, metformin hydrochloride, or a sulfonylurea and metformin hydrochloride upon initiation of rosiglitazone.¹

Combination therapy with a sulfonylurea: Initially, 4 mg of rosiglitazone daily in 1 or 2 divided doses.¹ If response is inadequate after 8–12 weeks, increase to a maximum of 8 mg of rosiglitazone daily.¹ If hypoglycemia occurs, reduce sulfonylurea dosage.¹

Combination therapy with metformin hydrochloride: Initially, 4 mg of rosiglitazone daily in 1 or 2 divided doses.¹ If response is inadequate after 8–12 weeks, increase to a maximum of 8 mg of rosiglitazone daily.¹ Need for adjustment of metformin hydrochloride dosage because of hypoglycemia unlikely.¹

Combination therapy with a sulfonylurea and metformin hydrochloride: Initially, 4 mg of rosiglitazone daily in 1 or 2 divided doses.¹ If response is inadequate after 8–12 weeks, increase to a maximum of 8 mg of rosiglitazone daily.¹ If hypoglycemia occurs, reduce sulfonylurea dosage.¹

Combination therapy with glyburide/metformin hydrochloride fixed combination: Initially, 4 mg of rosiglitazone and existing daily dosage of fixed combination.^m If response inadequate, increase to a maximum of 8 mg of rosiglitazone daily.^m If hypoglycemia develops, reduce glyburide dosage; consider dosage adjustments of other agents as clinically indicated.^m

Rosiglitazone/Metformin Hydrochloride Fixed-combination Therapy (Avandamet)

Oral

Previously untreated patients: Usual initial dosage is 2 mg of rosiglitazone and 500 mg of metformin hydrochloride once or twice daily.¹¹⁰ For more severe hyperglycemia (i.e., HbA_1c >11% or fasting plasma glucose [FPG] concentrations >270 mg/dL), consider 2 mg of rosiglitazone and 500 mg of metformin hydrochloride twice daily.¹¹⁰ If additional glycemic control needed after 4 weeks, titrate dosage upward in increments of 2 mg of rosiglitazone and 500 mg of metformin hydrochloride per day until adequate glycemic control is achieved or a maximum daily dosage of 8 mg of rosiglitazone and 2 g of metformin hydrochloride is reached.¹¹⁰

Patients inadequately controlled on metformin or rosiglitazone monotherapy: Dosage of the fixed combination is based on the patient’s current dosage of metformin hydrochloride or rosiglitazone.¹¹⁰ (See Table 1.)

Patients inadequately controlled on metformin monotherapy: Usual initial dosage of rosiglitazone is 4 mg daily given with patient's existing dosage of metformin hydrochloride.¹¹⁰

Patients inadequately controlled on rosiglitazone monotherapy: Usual initial dosage of metformin hydrochloride is 1 g daily given with patient's existing dosage of rosiglitazone.¹¹⁰

Individualize therapy in patients already receiving metformin hydrochloride at dosages not available in the fixed combination (i.e., dosages other than 1 or 2 g).¹¹⁰

Table 1. Initial Dosage of the Fixed Combination of Rosiglitazone and Metformin Hydrochloride (Avandamet)110

Prior Therapy	Usual Initial Dosage of Avandamet
Total Daily Dosage	Tablet Strength	Number of Tablets
Metformin Hydrochloride
1 g	2 mg/500 mg	1 tablet twice daily
2 g	2 mg/1 g	1 tablet twice daily
Rosiglitazone
4 mg	2 mg/500 mg	1 tablet twice daily
8 mg	4 mg/500 mg	1 tablet twice daily

Tablet strength of fixed-combination preparation that is selected should be the one that most closely provides patient’s existing dosage of rosiglitazone or metformin hydrochloride, respectively.¹¹⁰ (See Table 1.)

If additional glycemic control is needed following transfer, titrate dosage upward in increments of 4 mg of rosiglitazone and/or 500 mg of metformin hydrochloride per day until adequate glycemic control is achieved or a maximum daily dosage of 8 mg of rosiglitazone and 2 g of metformin hydrochloride is reached.¹¹⁰ Following increase in dosage of metformin hydrochloride, further dosage adjustment recommended if adequate glycemic control not achieved in 1–2 weeks.^c Following increase in dosage of rosiglitazone, further dosage adjustment recommended if adequate glycemic control not achieved in 8–12 weeks.^c

For replacement of concurrent therapy with the drugs given as separate tablets, dosage of the fixed combination is based on the patient’s current dosages of metformin hydrochloride and/or rosiglitazone.¹¹⁰

Rosiglitazone/Glimepiride Fixed-combination Therapy (Avandaryl)

Oral

Previously untreated patients: Usual initial dosage is 4 mg of rosiglitazone and 1 mg of glimepiride once daily.¹¹⁸

Patients inadequately controlled on sulfonylurea or rosiglitazone monotherapy: Initially, 4 mg of rosiglitazone and 1 or 2 mg of glimepiride once daily.¹¹⁸

In patients previously receiving thiazolidinedione monotherapy, allow approximately 1–2 weeks to assess therapeutic response to newly initiated glimepiride component before adjusting dosage.¹¹⁸ If additional glycemic control is needed after 1–2 weeks, increase dosage of the glimepiride component in increments of ≤2 mg.¹¹⁸ Assess response to increase in glimepiride component after 1–2 weeks to determine need for further dosage adjustment.^d If additional glycemic control is needed, increase dosage of glimepiride and rosiglitazone until adequate glycemic control is achieved or maximum daily dosage of 8 mg of rosiglitazone and 4 mg of glimepiride is reached.^d

In patients previously receiving sulfonylurea monotherapy, allow 2 weeks to observe reduction in blood glucose concentrations and 2–3 months to observe full therapeutic response to newly initiated rosiglitazone component.^{118 d} If additional glycemic control is needed after 8–12 weeks, increase dosage of the rosiglitazone component.¹¹⁸ If additional glycemic control is needed 2–3 months after an increase in rosiglitazone component, increase dosage of glimepiride and rosiglitazone.^d During transfer from chlorpropamide (a sulfonylurea with a long elimination half-life), closely monitor for hypoglycemia during the initial 1–2 weeks of the transition period.¹¹⁸

For replacement of concurrent therapy with the drugs given as separate tablets, dosage of the fixed combination is based on the patient’s current dosages of glimepiride and/or rosiglitazone.¹¹⁸

If hypoglycemia occurs, reduce dosage of the glimepiride component. ¹¹⁸

Prescribing Limits

Adults

Treatment of Diabetes Mellitus

Oral

Rosiglitazone monotherapy: Maximum 8 mg daily;¹ no additional benefit observed with dosage of 12 mg daily.^{1 30}

Combination with a sulfonylurea, metformin hydrochloride, or sulfonylurea and metformin hydrochloride, given separately: Maximum 8 mg of rosiglitazone daily.¹

Fixed-combination preparation with metformin hydrochloride: Maximum 8 mg of rosiglitazone and 2 g of metformin hydrochloride daily.¹¹⁰

Fixed-combination preparation with glimepiride: Maximum 8 mg of rosiglitazone and 4 mg of glimepiride daily.¹¹⁸

Special Populations

Hepatic Impairment

Rosiglitazone monotherapy: Do not initiate therapy in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).¹

Fixed-combination preparation with glimepiride: Initially, 4 mg of rosiglitazone and 1 mg of glimepiride once daily.¹¹⁸ Conservative initial and maintenance dosages recommended in patients with mild hepatic impairment; these individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.¹¹⁸ Do not initiate therapy with fixed combination in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).¹¹⁸

Fixed-combination preparation with metformin hydrochloride: Do not initiate therapy with fixed combination in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).¹¹⁰

Renal Impairment

Rosiglitazone monotherapy: No dosage adjustment necessary.¹

Fixed-combination preparation with glimepiride: Initially, 4 mg of rosiglitazone and 1 mg of glimepiride once daily.¹¹⁸ Conservative initial and maintenance dosages recommended; individuals with renal impairment may be particularly sensitive to the hypoglycemic effects of glimepiride.^d

Geriatric Patients

Rosiglitazone monotherapy: No dosage adjustment necessary.¹

Fixed-combination preparation with metformin hydrochloride: Conservative initial and maintenance dosages recommended.¹¹⁰ Generally, do not titrate to maximum recommended dosage.¹¹⁰

Fixed-combination preparation with glimepiride: Initially, 4 mg of rosiglitazone and 1 mg of glimepiride once daily.¹¹⁸ Conservative initial and maintenance dosages recommended; geriatric individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.¹¹⁸

Other Populations

Fixed-combination preparation with metformin hydrochloride: Do not titrate to maximum recommended dosage in debilitated or malnourished patients.¹¹⁰

Fixed-combination preparation with glimepiride: Initially, 4 mg of rosiglitazone and 1 mg of glimepiride once daily in debilitated or malnourished patients or patients with adrenal insufficiency.¹¹⁸ Conservative initial and maintenance dosages recommended; these individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.¹¹⁸

Cautions for Rosiglitazone Maleate

Contraindications

• 
  

  Initiation of therapy in patients with NYHA class III or IV CHF.^{1 110 118 128 a c d} (See Boxed Warning.)

  
  

Warnings/Precautions

Warnings

Heart Failure and Other Cardiac Effects

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Risk of fluid retention; may cause or exacerbate CHF.^{1 117 128 141 143} Use of thiazolidinediones associated with approximately twofold increased risk of CHF.^{131 143 k} (See Boxed Warning and also Edema under Cautions.)

Use with caution in patients with edema and in those who are at risk for CHF.^{1 117 c k} Initiation of rosiglitazone not recommended in patients experiencing an acute coronary event.^a If an acute coronary event occurs, consider discontinuance of rosiglitazone during the acute phase.^a Use not recommended in patients with NYHA class III or IV cardiac status.^{110 113 118 a n} Thiazolidinedione therapy should not be initiated in hospitalized patients with diabetes mellitus because of delayed onset of action and potential for increased vascular volume and CHF.¹¹⁴

In patients with NYHA class I or II CHF, increased incidence of adverse cardiovascular events (e.g., edema, need for additional CHF therapy) reported in patients receiving rosiglitazone in addition to other antidiabetic and CHF agents compared with incidence in those receiving placebo and other antidiabetic and CHF agents.^{1 110 118 128 142} Change in left ventricular ejection fraction did not differ between those receiving rosiglitazone and those receiving placebo.^{1 110 118 128 142}

Potential for increased risk of MI.^{129 130 131 132 133 134} (See Boxed Warning.) Increased risk of adverse cardiac effects observed in those receiving rosiglitazone and insulin.^{110 118 128 a} (See Specific Drugs under Interactions.)

General Precautions

Edema

Fluid retention reported; may lead to or exacerbate CHF.^{1 110 116 117 118 128} Weight gain reported; may involve fluid retention and fat accumulation.^{1 117 118 c}

Use with caution in patients with edema and in those at risk for CHF.^{1 110 117} Monitor for weight gain and edema.¹¹⁷ Evaluate any patient developing edema within first few months of therapy for possible CHF.¹¹⁷ (See Heart Failure and Other Cardiac Effects under Cautions.)

Musculoskeletal Effects

Bone loss and fractures reported in women.^{1 110 118 125 126 127 139 l} Fractures reported more frequently in women receiving long-term therapy (4–6 years) with rosiglitazone (9.3%) than in women receiving metformin (5.09%) or glyburide (3.47%).^{125 126 d l} Effects noted after first year of treatment and persisted throughout treatment.^{c d} Majority of fractures were in upper limb (upper arm, hand, wrist) or distal lower limb (foot, ankle, fibula, tibia).^{1 110 118 125 127 l} Increased risk of fracture not identified in men.^{126 c d l}

Consider risk of fracture in female patients.^{1 110 118 125 127 l} Assess and maintain bone health according to current standards of care.^{110 125 a l}

Hematologic Effects

Possible dose-related decreases in hemoglobin (≤1 g/dL) and hematocrit (≤3.3%); usually evident within 3 months after initiation of therapy or dosage increase.^{1 30 110 a} Possible modest decreases in leukocyte counts.¹ Hematologic effects may be related to plasma volume expansion.^{1 30}

Ocular Effects

New-onset or worsening (diabetic) macular edema with decreased visual acuity reported; some patients reported concurrent peripheral edema.^{1 110 118 119 i} Some patients were symptomatic (e.g., blurred vision, decreased visual acuity); other cases were detected by routine ophthalmologic examination.^{1 110 118} Symptoms improved in some patients after discontinuance or rarely after dosage reduction.^{1 110 118 119}

Regular eye examinations by an ophthalmologist recommended in patients with diabetes mellitus.^{1 110 114 118} Patients with any visual symptoms should be promptly evaluated by an ophthalmologist.^{1 110 118}

Ovulatory Effects

Possible ovulation in premenopausal anovulatory women; risk of pregnancy unless contraceptive measures initiated.¹ If unexpected menstrual dysfunction occurs, weigh risks versus benefits of continued therapy.¹

Hepatic Effects

No evidence of hepatotoxicity in clinical studies to date.^{1 30 104 109} However, hepatitis, elevations in hepatic enzymes, and, very rarely, hepatic failure associated with fatalities reported during postmarketing experience.¹

Monitor liver function prior to initiation of therapy and periodically thereafter according to clinician judgment.¹ Monitor more frequently if used in patients with mild hepatic impairment (ALT ≤2.5 times ULN).¹ (See Hepatic Impairment under Cautions.)

Recheck ALT as soon as possible if ALT increases to >3 times the ULN.¹ Discontinue therapy if ALT remains elevated at >3 times ULN.¹ Check liver function if manifestations suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine) occur.¹ Decision to continue therapy pending results of laboratory tests should be guided by clinician judgment.^a Discontinue if jaundice develops.^{1 110}

Use of Fixed Combinations

When used in fixed combination with metformin hydrochloride or glimepiride, consider the cautions, precautions, and contraindications associated with the concomitant agent.^{110 118}

Specific Populations

Pregnancy

Category C.^{1 110 d} Risk of birth defects, pregnancy loss, or other adverse outcomes increases in pregnancies complicated by hyperglycemia and may decrease with good glycemic control.^{a c} Most clinicians recommend use of insulin during pregnancy to maintain optimum control of blood glucose concentrations.^{1 c} Use of rosiglitazone in pregnant women not recommended.^{1 110 118}

Lactation

Distributed into milk in rats; not known whether distributed into human milk.^{1 110 d i} Use not recommended.^{1 110 d i}

Pediatric Use

Rosiglitazone: Has been evaluated in children and adolescents 10–17 years of age.^a Manufacturer states that data are insufficient to recommend use in pediatric patients <18 years of age.¹

Fixed combination with glimepiride: Safety and efficacy not established in pediatric patients <18 years of age.^{118 137}

Fixed combination with metformin hydrochloride: Safety and efficacy not established in pediatric patients.^c

ADA states that use of oral antidiabetic agents may be considered in children with type 2 diabetes mellitus because of the greater compliance and convenience and lack of evidence demonstrating better efficacy of insulin for type 2 diabetes mellitus.¹⁰⁷

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.^a Select dosage with care.^a (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution in patients with mild hepatic impairment (ALT ≤2.5 times the ULN).^{1 c d} Use not recommended in patients with active hepatic disease, ALT >2.5 times ULN, or troglitazone-associated jaundice.^{1 110 d}

Common Adverse Effects

Upper respiratory tract infection,^{1 30} injury,¹ headache.^{1 a}

Interactions for Rosiglitazone Maleate

Metabolized principally by CYP2C8 and, to a lesser extent, by CYP2C9.^{1 c d} Does not inhibit CYP isoenzymes.^{1 c d}

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP2C8: Potential pharmacokinetic interaction.¹⁰⁴ Changes in antidiabetic therapy may be necessary when these drugs are initiated or discontinued during rosiglitazone therapy.^{1 d}

Drugs metabolized by CYP3A4: Pharmacokinetic interaction unlikely.^{1 30}

Specific Drugs

Drug	Interaction	Comments
Acarbose	Clinically important pharmacokinetic interaction unlikely1
Alcohol	Pharmacologic interaction (i.e., increased risk of hypoglycemia) unlikely1
Antidiabetic agents (See entries for acarbose, glimepiride, glyburide, and metformin)	Possible hypoglycemia1	May need to reduce dosage of concomitant antidiabetic agents1
Calcium-channel blockers	May exacerbate diabetes mellitus110	Observe closely when concurrent therapy is initiated or discontinued110
Corticosteroids	May exacerbate diabetes mellitus110 d	Observe closely when concurrent therapy is initiated or discontinued110
Digoxin	Pharmacokinetic interaction unlikely1 30
Diuretics, thiazide	May exacerbate diabetes mellitus110 d	Observe closely when concurrent therapy is initiated or discontinued 110
Gemfibrozil	Potential increased AUC of rosiglitazone1 110	May need to reduce rosiglitazone dosage when gemfibrozil therapy is initiated1 110
Glimepiride	Additive glycemic control1 118 Pharmacokinetic interaction unlikely1 118	Used to therapeutic advantaged
Glyburide	Variable effects on peak plasma concentrations and AUC of glyburide, depending on racea d Enhanced glycemic control following long-term combined therapy30 104 105 106
Insulin	Increased risk of CHF and other cardiovascular effects (e.g., myocardial ischemia)110 118 128 a	Concomitant use not recommendeda
Isoniazid	May exacerbate diabetes mellitus110	Observe closely when concurrent therapy is initiated or discontinued110
Metformin	Pharmacokinetic interaction unlikely1 Additive glycemic control1 30	Used to therapeutic advantagec
Niacin	May exacerbate diabetes mellitus110	Observe closely when concurrent therapy is initiated or discontinued110
Nitrates	Possible increased risk of myocardial ischemiaa	Concomitant use not recommendeda
Nifedipine	Pharmacokinetic interaction unlikely1
Oral contraceptives, hormonal (ethinyl estradiol, norethindrone)	Pharmacokinetic interaction unlikely1 Estrogens may exacerbate diabetes mellitus110 d	Observe closely when concurrent therapy is initiated or discontinued110
Phenothiazines	May exacerbate diabetes mellitus110 d	Observe closely when concurrent therapy is initiated or discontinued110
Phenytoin	May exacerbate diabetes mellitus110 d	Observe closely when concurrent therapy is initiated or discontinued110
Ranitidine	Pharmacokinetic interaction unlikely1
Rifampin	Potential decreased rosiglitazone AUC1 110 d	May need to adjust dosage of rosiglitazone during initiation or discontinuance of rifampin1 110 d
Sympathomimetic agents	May exacerbate diabetes mellitus110 d	Observe closely when concurrent therapy is initiated or discontinue110
Thyroid hormones	May exacerbate diabetes mellitus110 d	Observe closely when concurrent therapy is initiated or discontinued110
Warfarin	Pharmacokinetic interaction unlikely1

Rosiglitazone Maleate Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained about 1 hour after dosing.¹

Absolute bioavailability is 99%.^{1 110 b d}

Fixed-combination preparation containing 4 mg of rosiglitazone and 4 mg of glimepiride i