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

Warning(s)

Special Alerts:

[Posted 11/25/2013] ISSUE: FDA has determined that recent data for rosiglitazone-containing drugs, such as Avandia, Avandamet, Avandaryl, and generics, do not show an increased risk of heart attack compared to the standard type 2 diabetes medicines metformin and sulfonylurea. As a result, FDA is requiring removal of the prescribing and dispensing restrictions for rosiglitazone medicines that were put in place in 2010. This decision is based on FDA review of data from a large, long-term clinical trial and is supported by a comprehensive, outside, expert re-evaluation of the data conducted by the Duke Clinical Research Institute (DCRI).

Previous data from a large, combined analysis of mostly short-term, randomized clinical trials of rosiglitazone had suggested an elevated risk of heart attack, so FDA required a Risk Evaluation and Mitigation Strategy (REMS), called the Rosiglitazone REMS program. The Rosiglitazone REMS program restricted the use of rosiglitazone medicines to help ensure that their benefits outweighed the risks.

Although some scientific uncertainty about the cardiovascular safety of rosiglitazone medicines still remains, in light of the new re-evaluation of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial, FDAs concern is substantially reduced and the rosiglitazone REMS program requirements will be modified. FDA is also requiring revisions to the rosiglitazone prescribing information and the patient Medication Guide to include this new information

BACKGROUND: Rosiglitazone is a treatment option that can improve blood sugar control in some patients with type 2 diabetes.

RECOMMENDATION: Patients with type 2 diabetes should continue to work closely with their health care professionals to determine treatment options that are most appropriate. Health care professionals, pharmacies, and patients will no longer be required to enroll in the rosiglitazone REMS program to be able to prescribe, dispense, or receive rosiglitazone medicines. As part of the REMS, sponsors will ensure that health care professionals who are likely to prescribe rosiglitazone medicines are provided training based on the current state of knowledge concerning the cardiovascular risk of rosiglitazone medicines. Manufacturers will also send Dear Healthcare Provider and Dear Professional Society letters to educate prescribers about the new information.

For more information visit the FDA website at: and .

REMS:

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

Warning(s)

  • CHF
  • Thiazolidinediones, including rosiglitazone, cause or exacerbate CHF in some patients.1 110 116 117 118 128 141 143 Monitor patients for signs and symptoms of CHF (e.g., excessive, rapid weight gain; dyspnea; and/or edema) after initiation of therapy and dosage titration.1 110 117 118 128 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.1 110 117 118 128

  • Not recommended in patients with symptomatic CHF.1 110 113 118

  • Initiation of rosiglitazone in patients with NYHA class III or IV CHF contraindicated.1 110 118 128 (See Heart Failure and MI under Cautions.)

  • MI
  • Potential increased risk of MI.1 110 118 148 217 Findings from a meta-analysis of 52 clinical trials (average duration 6 months; majority placebo-controlled) indicate that risk of MI is increased in patients receiving rosiglitazone.1 110 118 217 130 134 144 Although not statistically significant, higher rate of MI also observed with rosiglitazone versus placebo or active comparators in 3 large, long-term clinical trials.1 110 118 123 126 131

  • Similar risk with pioglitazone not observed to date; directly comparative studies not performed.1 110 118 206 210

  • Because of potential for increased risk of MI, rosiglitazone can only be obtained through the Avandia-Rosiglitazone Medicines Access Program.1 110 118 215 (See Restricted Distribution Program under Dosage and Administration.)

Introduction

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

Uses for Rosiglitazone Maleate

Treatment of Diabetes Mellitus

Used in appropriately selected patients as monotherapy 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).1 30 106 110 111 112 118 121 122

Use of rosiglitazone (alone or in combination) is restricted to patients who are already being treated successfully with the drug and to those not already receiving rosiglitazone who are unable to achieve glycemic control with other antidiabetic agents and have decided (in consultation with their healthcare provider) not to take pioglitazone for medical reasons; should be used in such patients only after they have been advised of and have carefully considered the potential risks versus benefits.1 110 118 215 (See Restricted Distribution Program under Dosage and Administration.)

Slideshow: Can Prescription Drugs Lead to Weight Gain?

May be added to glyburide/metformin fixed-combination therapy in appropriately selected patients if hyperglycemia is not adequately controlled with the fixed combination.111

May be used in combination with repaglinide in appropriately selected patients if hyperglycemia is not adequately controlled with repaglinide monotherapy.115

May use fixed combination of rosiglitazone/metformin (Avandamet) when treatment with rosiglitazone and metformin is appropriate.110

May use fixed combination of rosiglitazone/glimepiride (Avandaryl) when treatment with rosiglitazone and glimepiride is appropriate.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).1 148

Use in combination with insulin not recommended.1 110 118 (See Heart Failure and MI under Cautions and also see Specific Drugs under Interactions.)

Because endogenous insulin is required for activity, not indicated for type 1 diabetes mellitus or diabetic ketoacidosis.1 110 118 146

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 MI under Cautions.)

Rosiglitazone Maleate Dosage and Administration

General

  • Because of risk of MI, appropriate patient selection is mandatory prior to initiation of therapy; carefully consider and advise patient of risks and benefits of therapy.1 110 118 215

  • Monitor regularly (e.g., fasting blood glucose concentrations, HbA1c) to determine therapeutic response.1 110 118 146

  • Carefully monitor for fluid retention after dosage increases.1 110 118

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

Restricted Distribution Program

Distribution of rosiglitazone is restricted because of potential increased risk of MI.1 110 118 215 (See REMS and see also Heart Failure and MI under Cautions.)

Rosiglitazone and fixed-combination preparations containing rosiglitazone (Avandaryl, Avandamet) can only be obtained through certified pharmacies registered with the Avandia-Rosiglitazone Medicines Access Program.1 110 118 215 Clinicians and patients must enroll in the program before they can prescribe and receive these drugs for outpatient or long-term care use.1 110 118 215

For additional information, contact the Avandia-Rosiglitazone Medicines Access Program at 800-Avandia or visit www.avandia.com.1 110 118

Administration

Oral Administration

Administer rosiglitazone once or twice daily without regard to meals.1 25 146

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

Administer rosiglitazone/glimepiride fixed-combination preparation once daily with the first meal of the day.118 137

If a dose is missed, take the missed dose as soon as it is remembered.136 137 146 If the missed dose is remembered at the time of the next dose, skip missed dose and resume the regular schedule.136 137 146 Do not double dose to replace missed dose.136 137 146

Dosage

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.1 146 If response is inadequate after 8–12 weeks, may increase dosage to a maximum of 8 mg daily.1

Rosiglitazone/Metformin Hydrochloride Fixed-combination Therapy (Avandamet)
Oral

Dosage of the fixed combination is based on the patient’s current dosage of metformin hydrochloride and/or rosiglitazone.110 (See Table 1.) Initiate rosiglitazone component at the lowest recommended dosage.110

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

Patients currently receiving 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 in doses not available in the fixed combination (i.e., doses 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

Patients switching from combined therapy with separate rosiglitazone and metformin preparations: Usual initial dosage of the fixed combination is the same as the patient's existing dosage of the individual drugs.110

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

Rosiglitazone/Glimepiride Fixed-combination Therapy (Avandaryl)
Oral

Initially, 4 mg of rosiglitazone and 1 mg of glimepiride once daily.118 May consider initial dosage of 4 mg of rosiglitazone and 2 mg of glimepiride once daily in patients already receiving a sulfonylurea or rosiglitazone.118

Initiate rosiglitazone component at the lowest recommended dosage.118

Patients switching from combined therapy with separate rosiglitazone and glimepiride preparations: Usual initial dosage of the fixed-combination is the same as the patient's existing dosage of the individual drugs.118

In patients previously receiving rosiglitazone monotherapy, allow approximately 1–2 weeks to assess therapeutic response.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.118

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 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, further titrate dosage.118

During transfer from therapy with a sulfonylurea with a long half-life (e.g., chlorpropamide), closely monitor for hypoglycemia during the initial 1–2 weeks of the transition period.118

If hypoglycemia occurs, consider dosage reduction of the glimepiride component. 118

Prescribing Limits

Adults

Treatment of Diabetes Mellitus
Oral

Rosiglitazone monotherapy: Maximum 8 mg 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 metformin hydrochloride: Do not initiate therapy in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).110

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

Renal Impairment

Rosiglitazone monotherapy: No dosage adjustment necessary.1

Fixed-combination preparation with metformin hydrochloride: Base any dosage adjustment on careful assessment of renal function.110

Fixed-combination preparation with glimepiride: Conservative initial and maintenance dosages recommended; individuals with renal impairment may be particularly sensitive to the hypoglycemic effects of glimepiride.118

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: 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: Conservative initial and maintenance dosages recommended in debilitated or malnourished patients or patients with adrenal insufficiency; 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.1 110 118 128 157 (See Boxed Warning.)

Warnings/Precautions

Warnings

Heart Failure and MI

Potential for increased risk of MI.1 110 118 129 130 131 132 133 134 148 151 155 205 206 207 209 210 211 (See Boxed Warning.) Because of this risk, use of rosiglitazone and fixed-combination preparations containing rosiglitazone is restricted to patients who are already being treated successfully with the drug and to those not already receiving rosiglitazone who are unable to achieve glycemic control with other antidiabetic agents and have decided (in consultation with their healthcare provider) not to take pioglitazone for medical reasons.1 205 206 215 (See Restricted Distribution Program under Dosage and Administration.)

Risk of fluid retention; may cause or exacerbate CHF.1 116 117 128 141 143 Use of thiazolidinediones associated with approximately twofold increased risk of CHF.131 143 148 151 155 (See Boxed Warning and also Edema under Cautions.)

Use with caution in patients with edema and in those who are at risk for CHF.1 110 117 148 Initiation of rosiglitazone not recommended in patients experiencing an acute coronary event.1 If an acute coronary event occurs, consider discontinuance of rosiglitazone during the acute phase.1 Use not recommended in patients with NYHA class III or IV cardiac status or those with symptomatic heart failure.1 110 113 118 149 150 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

Increased incidence of adverse cardiovascular events (e.g., edema, need for additional CHF therapy) reported in patients with NYHA class I or II CHF receiving rosiglitazone in addition to other antidiabetic and CHF agents.1 110 118 128 142 No change in left ventricular ejection fraction observed.1 110 118 128 142

Increased risk of adverse cardiac effects (e.g., MI, heart failure, major adverse cardiovascular events, death) observed in patients receiving rosiglitazone and insulin compared with those receiving insulin alone.1 110 118 128 (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.1 110 117 118

Use with caution in patients with edema and in those at risk for CHF.1 110 117 148 Monitor for weight gain and edema.1 117 Evaluate any patient developing edema within first few months of therapy for possible CHF.117 (See Heart Failure and MI under Cautions.)

Musculoskeletal Effects

Risk of bone loss and fractures in women, and possibly men.1 110 118 125 126 127 139 145 147 151 Fractures reported more frequently in women receiving long-term therapy (4–6 years) with rosiglitazone (9.3%) than in women receiving metformin (5.1%) or glyburide (3.5%).1 110 118 125 126 147 Effects noted after first year of treatment and persisted throughout treatment.1 110 118 Majority of fractures were in upper limb (upper arm, hand, wrist) or distal lower limb (foot, ankle, fibula, tibia).1 110 118 125 127 147 Although increased risk of fracture may also apply to men, risk appears higher among women than men.1

Consider risk of fracture.1 110 118 125 127 147 Assess and maintain bone health according to current standards of care.1 110 125 147

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 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 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 30 104 109 126 However, hepatitis, elevations in hepatic enzymes, and hepatic failure associated with fatalities reported during postmarketing experience.1

Monitor liver function tests prior to initiation of therapy and periodically thereafter according to clinician judgment.1 Do not initiate therapy if baseline ALT concentrations >2.5 times ULN.1 Evaluate patients with mildly elevated liver enzymes (e.g., ALT ≤2.5 ULN) prior to or during therapy to determine cause; initiate or continue drug with caution and close clinical monitoring.1 (See Hepatic Impairment under Cautions.)

Recheck liver enzymes 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.1 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 Risk of birth defects, pregnancy loss, or other adverse outcomes increases in pregnancies complicated by hyperglycemia and may decrease with good glycemic control.1 110 118 Most clinicians recommend use of insulin during pregnancy to maintain optimum control of blood glucose concentrations.1 110 118

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 110 118 146 Use not recommended.1 110 146

Pediatric Use

Rosiglitazone: Has been evaluated in children and adolescents 10–17 years of age.1 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.110

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.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution in patients with mild hepatic impairment (ALT ≤2.5 times the ULN).1 110 118 Use not recommended in patients with ALT >2.5 times ULN.1 110 118 (See Hepatic Effects under Cautions.)

Common Adverse Effects

Upper respiratory tract infection,1 30 injury,1 headache.1

Interactions for Rosiglitazone Maleate

Metabolized principally by CYP2C8 and, to a lesser extent, by CYP2C9.1 110 118 Does not inhibit CYP isoenzymes.1 110 118

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.1 118

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 cause hyperglycemia and lead to loss of glycemic control110

Corticosteroids

May cause hyperglycemia and lead to loss of glycemic control110 118

Digoxin

Pharmacokinetic interaction unlikely1 30

Diuretics, thiazide

May cause hyperglycemia and lead to loss of glycemic control110 118

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 advantage118

Glyburide

Variable effects on peak plasma concentrations and AUC of glyburide, depending on race1 118

Enhanced glycemic control following long-term combined therapy30 104 105 106

Insulin

Increased risk of MI and other adverse cardiovascular effects110 118 128

Concomitant use not recommended1

Isoniazid

May cause hyperglycemia and lead to loss of glycemic control110

Metformin

Pharmacokinetic interaction unlikely1

Additive glycemic control1 30

Used to therapeutic advantage110

Niacin

May cause hyperglycemia and lead to loss of glycemic control110

Nifedipine

Pharmacokinetic interaction unlikely1

Oral contraceptives, hormonal (ethinyl estradiol, norethindrone)

Pharmacokinetic interaction unlikely1

Estrogens may cause hyperglycemia and lead to loss of glycemic control110 118

Phenothiazines

May cause hyperglycemia and lead to loss of glycemic control110 118

Phenytoin

May cause hyperglycemia and lead to loss of glycemic control110 118

Ranitidine

Pharmacokinetic interaction unlikely1

Rifampin

Potential decreased rosiglitazone AUC1 110 118

May need to adjust dosage of rosiglitazone during initiation or discontinuance of rifampin1 110 118

Sympathomimetic agents

May cause hyperglycemia and lead to loss of glycemic control110 118

Thyroid hormones

May cause hyperglycemia and lead to loss of glycemic control110 118

Warfarin

Pharmacokinetic interaction unlikely1

Rosiglitazone Maleate Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained about 1 hour after dosing.1

Absolute bioavailability is 99%.1 110 118 219

Fixed-combination preparation containing 4 mg of rosiglitazone and 4 mg of glimepiride is bioequivalent to the individual components administered separately at the same dosages in fasted state.118

Fixed-combination preparation containing 4 mg of rosiglitazone and 500 mg of metformin hydrochloride is bioequivalent to the individual components administered separately at the same dosages in fasted state.110

Onset

A therapeutic response usually is apparent within 2 weeks.1 110 118 136 Maximum response occurs within 2–3 months.1 110 118 136

Food

Food decreases peak plasma concentration and delays time to peak concentration; not clinically relevant.1 110 118 (See Administration under Dosage and Administration.)

Distribution

Extent

Distributed into milk in rats.1 110 Not known whether the drug distributes into human milk.1 110 118 Crosses human placenta and is detectable in fetal tissues.1 110 118 Clinical importance unknown.1 110 118

Plasma Protein Binding

Approximately 99.8% (mainly albumin).1 110 118

Elimination

Metabolism

Extensively metabolized, principally by CYP2C81 110 118 and, to a lesser extent, by CYP2C9.1 110 118

Elimination Route

Excreted primarily in urine (64%) and in feces (23%) as metabolites.1 110 118

Half-life

Approximately 3–4 hours.1 110 118 219

Special Populations

In patients with hepatic disease, elimination half-life is prolonged by about 2 hours.1 110 118 In patients with moderate to severe hepatic impairment (Child-Pugh class B or C), clearance of unbound drug decreased.1 110 118

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).1 110 118

Actions

  • Structurally and pharmacologically related to pioglitazone and troglitazone (no longer commercially available in the US); unrelated to other antidiabetic agents (e.g., sulfonylureas, biguanides, α-glucosidase inhibitors).1 2 3 4 6 7 9 10 11 13 14 16 20 30

  • A peroxisome proliferator-activated receptorγ (PPARγ) agonist; increases transcription of insulin-responsive genes.1 2 3 4 9 13 14 16 20 30

  • Increases insulin sensitivity in target tissues and decreases hepatic gluconeogenesis.1 2 6 7 10 11 13 16 20 30 Ameliorates insulin resistance associated with type 2 diabetes mellitus without increasing insulin secretion from pancreatic β cells.1 7 10 13 Does not lower glucose concentrations below euglycemia.1 7 Reduces circulating concentrations of insulin and C-peptide.1 10

  • Ineffective in absence of endogenous insulin.1

Advice to Patients

  • Importance of patient reading medication guide before starting rosiglitazone and each time prescription is refilled.146

  • Importance of informing patients of potential risks and advantages of rosiglitazone therapy and of alternative therapies.146 Importance of informing patients that use of rosiglitazone is restricted to adults with type 2 diabetes mellitus who are already taking and benefiting from the drug and to those not already receiving rosiglitazone who are unable to achieve adequate glycemic control with other antidiabetic agents and, in consultation with their healthcare provider, have decided not to take pioglitazone for medical reasons.1 Patients must be enrolled in the Avandia-Rosiglitazone Medicines Access Program in order to receive rosiglitazone or rosiglitazone-containing preparations.1 (See Restricted Distribution Program under Dosage and Administration.)

  • Importance of informing patients that rosiglitazone is not recommended for patients with symptomatic heart failure.1 146 149 150 Importance of identifying and reporting to a clinician potential symptoms of heart failure (e.g., unusually rapid increase in weight, edema, unusual fatigue, shortness of breath).1 128 136 137 146

  • Possible increased risk of MI, particularly in patients also taking insulin.1 146 Importance of contacting a clinician immediately if chest pain or chest pressure occurs.146

  • Importance of taking exactly as prescribed.136 Importance of immediately contacting a clinician or a poison control center if accidental overdosage occurs.136 137

  • Importance of taking a missed dose as soon as possible, unless it is almost time for next dose.1 137 146 Do not double dose to make up for the missed dose.137 146

  • Importance of diet and exercise regimen adherence.1 110 136 137 146 Importance of regular monitoring of blood glucose and HbA1c.1 110 136 137 146

  • Importance of informing patients that rosiglitazone is not recommended in patients taking insulin.1

  • Importance of continuing rosiglitazone therapy even if response is not evident in ≤2 weeks; full therapeutic response may not be evident for 2–3 months after initiation of therapy.1 136 137 146

  • Importance of regular eye examinations.1 110 118 136 137 Importance of reporting change in vision.1 146

  • Importance of liver function test monitoring and immediate reporting of potential manifestations of hepatotoxicity (e.g., nausea or vomiting, abdominal pain, unusual fatigue, loss of appetite, dark urine, yellowing of skin or whites of eyes).1 110 118 136 137

  • Risk of fractures (e.g., hand, upper arm, foot) in women.1 110 118 136 137 145 146 147

  • Risk of hypoglycemia in patients receiving concomitant antidiabetic agent therapy.1 Provide instructions regarding management of hypoglycemia, including recognition of symptoms, predisposing conditions, and treatment.1 136

  • Risk of pregnancy in premenopausal anovulatory women.1 110 137 Advise patients regarding use of effective contraception during therapy.1 110 118 136 137

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., insulin and other drugs that affect glucose concentrations; antihypertensive agents; antilipemic agents; agents for CHF, prevention of CHD, or stroke) and dietary or herbal supplements,137 as well as any concomitant illnesses (e.g., CHF or other cardiac disease, type 1 diabetes mellitus, history of diabetic ketoacidosis, macular edema, liver disease, irregular menstrual periods).1 136 137 146

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 110 136 137 146

  • Importance of informing patients of other important precautionary information.1 110 118 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Distribution of rosiglitazone and rosiglitazone-containing preparations is restricted.1 110 118 (See Restricted Distribution Program under Dosage and Administration.)

Rosiglitazone Maleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2 mg (of rosiglitazone)

Avandia

GlaxoSmithKline

4 mg (of rosiglitazone)

Avandia

GlaxoSmithKline

8 mg (of rosiglitazone)

Avandia

GlaxoSmithKline

Rosiglitazone Maleate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2 mg (of rosiglitazone) with 500 mg Metformin Hydrochloride

Avandamet

GlaxoSmithKline

2 mg (of rosiglitazone) with 1 g Metformin Hydrochloride

Avandamet

GlaxoSmithKline

4 mg (of rosiglitazone) with 1 mg Glimepiride

Avandaryl

GlaxoSmithKline

4 mg (of rosiglitazone) with 2 mg Glimepiride

Avandaryl

GlaxoSmithKline

4 mg of (rosiglitazone) with 4 mg Glimepiride

Avandaryl

GlaxoSmithKline

4 mg (of rosiglitazone) with 500 mg Metformin Hydrochloride

Avandamet

GlaxoSmithKline

4 mg (of rosiglitazone) with 1 g Metformin Hydrochloride

Avandamet

GlaxoSmithKline

8 mg of (rosiglitazone) with 2 mg Glimepiride

Avandaryl

GlaxoSmithKline

8 mg of (rosiglitazone) with 4 mg Glimepiride

Avandaryl

GlaxoSmithKline

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Avandamet 2-1000MG Tablets (GLAXO SMITH KLINE): 60/$161.64 or 180/$455.07

Avandamet 2-500MG Tablets (GLAXO SMITH KLINE): 60/$174.07 or 180/$472.47

Avandamet 4-1000MG Tablets (GLAXO SMITH KLINE): 60/$279.99 or 180/$808.28

Avandamet 4-500MG Tablets (GLAXO SMITH KLINE): 60/$279.99 or 180/$785.93

Avandaryl 4-1MG Tablets (GLAXO SMITH KLINE): 30/$155.31 or 90/$434.86

Avandaryl 4-2MG Tablets (GLAXO SMITH KLINE): 30/$156.00 or 90/$447.65

Avandaryl 4-4MG Tablets (GLAXO SMITH KLINE): 30/$155.31 or 90/$434.86

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 26, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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