AVANDIA (rosiglitazone maleate) is indicated for:

• use as monotherapy, in patients not controlled by diet and exercise alone, to reduce insulin resistance and lower elevated blood glucose in patients with type 2 diabetes mellitus.

  
  

• use in combination with metformin or a sulfonylurea when diet and exercise plus the single agent do not result in adequate glycemic control. For patients inadequately controlled on metformin or a sulfonylurea, AVANDIA should be added to, not substituted for, metformin or the sulfonylurea.

  
  

 

Caloric restriction, weight loss, and exercise improve insulin sensitivity and are essential for the proper treatment of a diabetic patient. These measures are important not only in the primary treatment of type 2 diabetes, but also in maintaining the efficacy of drug therapy. Prior to initiation of therapy with AVANDIA, secondary causes of poor glycemic control (e.g., infection) should be investigated and treated.

Results of the population pharmacokinetic analysis (n=716 <65 years; n=331 ≥65 years) showed that age does not significantly affect the pharmacokinetics of rosiglitazone. Therefore, no dosage adjustments are required for the elderly.

The safety and effectiveness of rosiglitazone have not been established in patients younger than 18 years of age, therefore, AVANDIA is not indicated in patients younger than 18 years of age.

Thiazolidinediones, including AVANDIA are contraindicated in:

• Patients with known hypersensitivity to this product or any of its ingredients.

  
  

• Patients with serious hepatic impairment (see Warnings and Precautions).

  
  

• Patients with New York Heart Association (NYHA) Class III and IV cardiac status.

  
  

• Pregnancy. Insulin is recommended during pregnancy to control blood glucose levels. Oral antidiabetic agents should not be given (see Warnings and Precautions, Special Populations, Pregnant Women).

  
  

 

AVANDIA is active only in the presence of insulin due to its mechanism of action. Therefore, AVANDIA should not be used in the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis.

Close monitoring of glycemic control and rosiglitazone dose adjustment may be needed when rosiglitazone is co-administered with CYP2C8 inhibitors or inducers (see Drug Interactions).

The use of AVANDIA in combination therapy with insulin is not indicated (see Clinical Trial Adverse Drug Reactions).

Thiazolidinediones, like AVANDIA, alone or in combination with other antidiabetic agents, can cause fluid retention, which can exacerbate or lead to congestive heart failure. The fluid retention may very rarely present as rapid and excessive weight gain. All patients should be monitored for signs and symptoms of adverse reactions relating to fluid retention and heart failure. In particular, patients who are at risk for heart failure including those receiving concurrent therapy which increases insulin levels (i.e. sulfonylureas), and those patients with mild to moderate heart failure (NYHA Class I and II) should be closely monitored.

Treatment with thiazolidinediones has been associated with cases of congestive heart failure, some of which were difficult to treat unless the medication was discontinued. AVANDIA should be discontinued if any deterioration in cardiac status occurs.

Patients with severe cardiac failure (including NYHA Class III and IV cardiac status) were not studied during the clinical trials. AVANDIA is contraindicated in patients with NYHA Class III and IV cardiac status and should be used with caution in any patient with NHYA Class I and II cardiac status.

AVANDIA should be used with caution in patients with edema. In healthy volunteers who received AVANDIA 8 mg once daily as monotherapy for 8 weeks, there was a statistically significant increase in median plasma volume (1.8 mL/kg) compared to placebo. In controlled clinical trials of patients with Type 2 diabetes, mild to moderate edema was observed at a greater frequency in patients treated with AVANDIA and may be dose related (see Adverse Reactions). For information on macular edema, see Warnings and Precautions, Ophthalmologic.

When a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold AVANDIA and temporarily administer insulin. AVANDIA may be reinstituted after the acute episode is resolved.

Because AVANDIA does not stimulate insulin secretion, hypoglycemia is not expected to occur when AVANDIA is prescribed as monotherapy. Patients receiving AVANDIA in combination with other hypoglycemic agents (e.g. insulin secreting agents) may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.

In clinical studies, improvements in hyperglycemia were associated with weight gain. Dose-related weight gain was seen with AVANDIA alone and in combination with other hypoglycemic agents. Weight gain with thiazolidinediones can result from increases in subcutaneous adipose tissue and/or from fluid retention. Treatment should be re-evaluated in patients with excessive weight gain (see Action and Clinical Pharmacology and Adverse Reactions).

In controlled trials, there were dose-related decreases in hemoglobin and hematocrit. The magnitude of the decreases (≤11 g/L for hemoglobin and ≤0.034 for hematocrit) was small for AVANDIA alone and AVANDIA in combination with metformin or in combination with sulfonylurea. The changes occurred primarily during the first 3 months of therapy or following an increase in AVANDIA dose and remained relatively constant thereafter. Decreases may be related to increased plasma volume observed during treatment with AVANDIA and have not been associated with any significant hematologic clinical effects (see Adverse Reactions, Abnormal Hematologic and Clinical Chemistry Findings). Patients with a hemoglobin value of <110 g/L for males and <100 g/L for females were excluded from the clinical trials.

Rare cases of severe hepatocellular injury have been reported with thiazolidinediones. In pre-approval clinical studies in 4598 patients treated with AVANDIA, representing approximately 3600 patient years of exposure, there was no evidence of drug-induced hepatotoxicity or elevation of ALT levels.

In the pre-approval controlled trials, 0.2% of patients treated with AVANDIA had elevations in ALT >3 times the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with AVANDIA were reversible and were not clearly causally related to therapy with AVANDIA. In the clinical program including long-term, open-label experience, the rate per 100 patient years exposure of ALT increase to > 3 times the upper limit of normal was 0.35 for patients treated with AVANDIA, 0.59 for placebo-treated patients, and 0.78 for patients treated with active comparator agents.

Although available clinical data show no evidence of AVANDIA induced hepatotoxicity or ALT elevations, rosiglitazone has a common thiazolidinedione structure to troglitazone, which has been associated with idiosyncratic hepatotoxicity and rare cases of liver failure, liver transplants, and death during clinical use.

Liver enzymes should be checked prior to the initiation of therapy with AVANDIA in all patients and periodically thereafter per the clinical judgement of the healthcare professional.

Therapy with AVANDIA should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5 times the upper limit of normal). Patients with mildly elevated liver enzymes (ALT levels ≤2.5 times the upper limit of normal) at baseline or during therapy with AVANDIA should be evaluated to determine the cause of the liver enzyme elevation.

Initiation of, or continuation of, therapy with AVANDIA in patients with mild liver enzyme elevations should proceed with caution and include appropriate close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3 times the upper limit of normal in patients on therapy with AVANDIA, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3 times the upper limit of normal, therapy with AVANDIA should be discontinued (see Dosage and Administration).

If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with AVANDIA should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.

New onset and/or worsening macular edema with decreased visual acuity has been reported rarely in postmarketing experience with AVANDIA. In some cases, the visual events resolved or improved following discontinuation of AVANDIA. Physicians should consider the possibility of macular edema if a patient reports disturbances in visual acuity (see Adverse Reactions, Post-Market Adverse Drug Reactions).

As with other thiazolidinediones, AVANDIA may result in resumption of ovulation in premenopausal, anovulatory women with insulin resistance (e.g., patients with polycystic ovary syndrome). As a consequence of their improved insulin sensitivity, these patients may be at risk of pregnancy if adequate contraception is not used.

Although hormonal imbalance has been seen in preclinical studies, no significant adverse experiences associated with menstrual disorders have been reported in clinical trial participants, including premenopausal women. If unexpected menstrual dysfunction occurs, the benefits of continued therapy should be reviewed.

There are no controlled trials of AVANDIA in pregnant women. Rosiglitazone has been reported to cross the human placenta and to be detectable in fetal tissues. AVANDIA is contraindicated for use in pregnant women. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. In animal studies AVANDIA was not teratogenic but treatment during mid-late gestation caused fetal death and growth retardation in both rats and rabbits at 19- and 73-fold clinical systemic exposure, respectively.

The effect of rosiglitazone on labor and delivery in humans is not known.

It is not known whether AVANDIA is excreted in human milk. Because many drugs are excreted in human milk, AVANDIA should not be administered to a nursing woman.

There are no data on the use of AVANDIA in patients under 18 years of age; therefore, AVANDIA is not indicated for use in patients under 18 years of age. Thiazolidinediones promote the maturation of preadipocytes and have been associated with weight gain. Obesity is a major problem in adolescents with type 2 diabetes.

In the pooled population pharmacokinetic analysis, there were no marked differences in the pharmacokinetics of AVANDIA between elderly and non-elderly patients.

Periodic fasting blood glucose and A1C measurements should be performed to monitor therapeutic response.

Liver enzyme monitoring is recommended prior to initiation of therapy with AVANDIA in all patients and periodically thereafter (see Warnings and Precautions, Hepatic).

In clinical trials, events of anemia and edema tended to be reported more frequently at higher doses, were generally mild to moderate in severity and usually did not require discontinuation of treatment with AVANDIA.

In double blind studies, anemia was reported in 1.9% of patients taking AVANDIA as monotherapy compared to 0.7% on placebo, 0.6% on sulfonylureas and 2.2% on metformin. Treatment was required for 0.3% of patients with an adverse event of anemia. These adverse experiences rarely led to withdrawal. Reports of anemia were greater in patients treated with a combination of AVANDIA and metformin (7.1%) compared to monotherapy with AVANDIA or AVANDIA in combination with a sulfonylurea (2.3%). Lower pre-treatment hemoglobin/hematocrit levels in patients enrolled in the metformin combination clinical trials may have contributed to the higher reporting rate of anemia in these studies.

In clinical trials, edema was reported in 4.8% of patients taking AVANDIA as monotherapy compared to 1.3% on placebo, 1.0% on sulfonylureas and 2.2% on metformin. Treatment was required for 1.2% of patients on rosiglitazone monotherapy with an adverse event of edema. These adverse experiences rarely led to withdrawal. In these clinical trials, few patients (1.0%) were enrolled with a presenting medical condition of congestive heart failure (NYHA Class I/II). Edema was more frequently observed when AVANDIA was used in combination with a sulfonylurea.

In clinical trials, an increased incidence of heart failure has also been observed when AVANDIA was added to a sulfonylurea. There were too few events to confirm a dose relationship; however, the incidence of heart failure appeared higher with AVANDIA 8 mg daily (see Warnings and Precautions, Cardiovascular and Edema).

In double blind studies where AVANDIA was administered for up to one year, serious adverse experiences of ischemic heart disease were reported in 1.3% of patients taking AVANDIA compared to 0.5% on placebo, 0.8% on sulfonylureas and 1.3% on metformin. In clinical trials, dose-related weight gain was seen with AVANDIA alone and in combination with other hypoglycemic agents (see Action and Clinical Pharmacology and Warnings and Precautions).

Increased appetite was observed in clinical trials of rosiglitazone as monotherapy or concomitantly with a sulfonylurea.

Hypoglycemia was generally mild to moderate in nature and was dose-related when rosiglitazone was used in combination with metformin or a sulfonylurea. Patients receiving rosiglitazone in combination with oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.

Constipation was observed to be generally mild to moderate in nature during clinical trials of rosiglitazone as monotherapy, or concomitantly with metformin or a sulfonylurea.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In clinical trials, approximately 4600 type 2 diabetic patients have been treated with AVANDIA as monotherapy or concomitantly with metformin, sulfonylureas or insulin; 3300 patients were treated for 6 months or longer and 2000 patients were treated for 12 months or longer. In general, AVANDIA was well tolerated. The overall incidence and types of adverse experiences reported in clinical trials are shown in Table 1.

Table 1: AVANDIA

Adverse Experiences (≥5% in any treatment group) Reported by Patients in Double-blind Clinical Trials with AVANDIA as Monotherapy

Preferred Term	AVANDIA N=2526		Placebo N=601		Metformin N=225		Sulfonylureas N=626
	n	%	n	%	n	%	n	%
Total Patients With Adverse Experiences	1742	69.0	374	62.2	172	76.0	438	70.0
Upper Respiratory Tract Infection	251	9.9	52	8.7	20	8.9	46	7.3
Injurya	192	7.6	26	4.3	17	7.6	38	6.1
Headache	148	5.9	30	5.0	20	8.9	34	5.4
Back Pain	102	4.0	23	3.8	9	4.0	31	5.0
Hyperglycemia	99	3.9	34	5.7	10	4.4	51	8.1
Fatigue	92	3.6	30	5.0	9	4.0	12	1.9
Sinusitis	82	3.2	27	4.5	12	5.3	19	3.0
Diarrhea	59	2.3	20	3.3	35	16	19	3.0
Hypoglycemia	16	0.6	1	0.2	3	1.3	37	5.9

^a. Includes cuts, burns, sprains, fractures, falls, accidents and surgical procedures.

Overall, the types of adverse experiences reported when AVANDIA was used in combination with a sulfonylurea or metformin were similar to those during monotherapy with AVANDIA.

Small decreases in hematological parameters were more common in the patients treated with AVANDIA than in placebo-treated patients. Leukopenia was reported in 0.4% of AVANDIA patients compared to 0.2% of patients on placebo, 0.6% on sulfonylureas and 0% on metformin. Decreases may be related to increased plasma volume observed with treatment with AVANDIA. The mean decrease in hemoglobin was approximately 10 to 12 g/L; the decrease in hematocrit was 0.03 to 0.04.

Small changes in serum lipids have been observed following treatment with AVANDIA (see Action and Clinical Pharmacology, Pharmacodynamics and Clinical Effects).

In clinical studies in 4598 patients treated with AVANDIA (rosiglitazone maleate) encompassing approximately 3600 patient years of exposure, there was no evidence of drug-induced hepatotoxicity or elevated ALT levels. In the controlled trials (including patients with ALT/AST of up to 2.5 times the upper limit of the reference range at study entry), 0.2% of patients treated with AVANDIA had reversible elevations in ALT >3 times the upper limit of the reference range compared to 0.2% on placebo, 0.9% on metformin and 0.3% on sulfonylureas. Hyperbilirubinemia was found in 0.3% of patients treated with AVANDIA compared with 0.9% treated with placebo. Overall, there was a decrease in mean values for ALT, AST, alkaline phosphatase and bilirubin over time in patients treated with AVANDIA (see Warnings and Precautions, Hepatic). In the clinical program including long-term, open-label experience, the rate per 100 patient years exposure of ALT increase to >3 times the upper limit of normal was 0.35 for patients treated with AVANDIA, 0.59 for placebo-treated patients, and 0.78 for patients treated with active comparator agents.

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure.

In postmarketing experience with AVANDIA as monotherapy and in combination with other antidiabetic agents, adverse events potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported (see Warnings and Precautions, Cardiovascular and Edema).

Postmarketing reports of new onset and/or worsening macular edema with decreased visual acuity occurring with the use of AVANDIA have been received rarely. These patients frequently reported concurrent peripheral edema. In some cases, symptoms improved following discontinuation of AVANDIA (see Warnings and Precautions, Ophthalmologic).

Postmarketing reports of anaphylactic reaction (such as angioedema and urticaria), rash and pruritus have been received very rarely.

In postmarketing experience with AVANDIA, reports of hepatitis and of hepatic enzyme elevations to three or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pending the availability of the results of additional large, long-term controlled clinical trials and additional postmarketing safety data following wide clinical use of AVANDIA to more fully define its hepatic safety profile, it is recommended that patients treated with AVANDIA undergo periodic monitoring of liver enzymes.

It has been shown in vitro that AVANDIA does not inhibit any of the major P₄₅₀ enzymes at clinically relevant concentrations. In vitro studies demonstrate that rosiglitazone is predominantly metabolized by CYP2C8, with CYP2C9 as only a minor pathway. In vitro studies have shown that montelukast is an inhibitor of CYP2C8 and may inhibit the metabolism of drugs primarily metabolized by CYP2C8 (e.g. paclitaxel, rosiglitazone, repaglinide). No in vivo interaction studies have been performed with the CYP2C8 inhibitor, montelukast or with CYP2C8 substrates cerivastatin and paclitaxel. The potential for a clinically relevant interaction with cerivastatin is considered to be low. Although rosiglitazone is not anticipated to affect the pharmacokinetics of paclitaxel, concomitant use is likely to result in inhibition of the metabolism of rosiglitazone.

Coadministration of rosiglitazone with CYP2C8 inhibitors (e.g. gemfibrozil) resulted in increased rosiglitazone plasma concentrations. Since there is a potential for an increase in the risk of dose-related adverse reactions, a decrease in rosiglitazone may be needed when CYP2C8 inhibitors are coadministered.

Coadministration of rosiglitazone with a CYP2C8 inducer (e.g. rifampin) resulted in decreased rosiglitazone plasma concentrations. Therefore, close monitoring of glycemic control and changes in diabetic treatment should be considered when CYP2C8 inducers are coadministered.

Clinically significant interactions with CYP2C9 substrates or inhibitors are not anticipated.

AVANDIA (8 mg once daily) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine and oral contraceptives (ethinylestradiol and norethindrone), which are predominantly metabolized by CYP3A4. The results of these two drug interaction studies suggest that AVANDIA is unlikely to cause clinically important drug interactions with other drugs metabolized via CYP3A4.

A single administration of a moderate amount of alcohol did not increase the risk of acute hypoglycemia in type 2 diabetes mellitus patients treated with AVANDIA.

In 32 healthy women, AVANDIA (8 mg once daily) was shown to have no statistically significant effect on the pharmacokinetics of oral contraceptives (ethinylestradiol and norethindrone). Breakthrough bleeding occurred in 5 individuals when AVANDIA was coadministered with an oral contraceptive. In one of these subjects a 40% decrease in ethinylestradiol exposure (AUC) was recorded. This was not correlated with a reduction in exposure to norethindrone, nor was there a consistent relationship between the occurrence of breakthrough bleeding and the pharmacokinetics of either ethinylestradiol or norethindrone in individual subjects.

AVANDIA (2 mg twice daily) taken concomitantly with glyburide (3.75 to 10 mg/day) for 7 days did not alter the mean steady-state 24-hour plasma glucose concentrations in diabetic patients stabilized on glyburide therapy.

Concurrent administration of AVANDIA (2 mg twice daily) and metformin (500 mg twice daily) in healthy volunteers for 4 days had no effect on the steady-state pharmacokinetics of either metformin or rosiglitazone.

Coadministration of acarbose (100 mg three times daily) for 7 days in healthy volunteers had no clinically relevant effect on the pharmacokinetics of a single oral dose of AVANDIA.

Repeat oral dosing of AVANDIA (8 mg once daily) for 14 days did not alter the steady-state pharmacokinetics of digoxin (0.375 mg once daily) in healthy volunteers.

Coadministration of AVANDIA (4 mg twice daily for 7 days) did not alter the anticoagulant response of steady-state warfarin in healthy volunteers with baseline values of INR of <2.75. Repeat dosing with AVANDIA had no clinically relevant effect on the steady-state pharmacokinetics of warfarin.

Pretreatment with ranitidine (150 mg twice daily for 4 days) did not alter the pharmacokinetics of either single oral or intravenous doses of rosiglitazone in healthy volunteers. These results suggest that the absorption of oral rosiglitazone is not altered in conditions accompanied by increases in gastrointestinal pH.

A study conducted in normal healthy volunteers showed that gemfibrozil (an inhibitor of CYP2C8) administered as 600 mg twice daily, increased rosiglitazone systemic exposure two-fold at steady state (see Warnings and Precautions, General).

A study conducted in normal healthy volunteers showed that rifampin (an inducer of CYP2C8) administered as 600 mg daily, decreased the rosiglitazone systemic exposure three-fold (see Warnings and Precautions, General).

An interaction study of 22 adult patients with psoriasis examined the effect of repeat doses of rosiglitazone (8 mg daily as a single dose for 8 days) on the pharmacokinetics of oral methotrexate administered as single oral doses of 5 to 25 mg weekly. Following 8 days of rosiglitazone administration, the C_max and AUC_(0-inf) of methotrexate increased by 18% (90% CI: 11% to 26%) and 15% (90% CI: 8% to 23%), respectively, when compared to the same doses of methotrexate administered in the absence of rosiglitazone.

Results of the population pharmacokinetic analysis indicated that none of the following classes of concomitant medications (oral hypoglycemics, analgesics, calcium channel blockers, hypolipidemics, ACE inhibitors and steroid hormones) appear to alter the oral clearance or oral steady-state volume of distribution of AVANDIA.

Interactions with food have not been established.

Interactions with herbal products have not been established.

Interactions with laboratory tests have not been established.

The management of antidiabetic therapy should be individualized.

AVANDIA may be administered as a single daily dose in the morning, or divided and administered in the morning and evening.

AVANDIA may be taken with or without food.

No dosage adjustments are required for the elderly, or in patients with renal impairment. Therapy with AVANDIA should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT > 2.5 times the upper limit of normal at start of therapy). See Warnings and Precautions, Hepatic and Action and Clinical Pharmacology, Special Populations and Conditions, Hepatic Insufficiency.

The usual starting dose of AVANDIA is 4 mg administered either as a single dose once daily or in divided doses twice daily. For patients who respond inadequately following 8 to 12 weeks of treatment as determined by reduction in fasting plasma glucose (FPG), the dose may be increased to 8 mg administered as a single dose once daily or in divided doses twice daily.

The usual starting dose of AVANDIA in combination with metformin is 4 mg administered as either a single dose once daily or in divided doses twice daily. The dose of AVANDIA may be increased to 8 mg/day following 8 to 12 weeks of therapy if there is insufficient reduction in FPG.

The recommended starting dose of AVANDIA when used in combination with sulfonylurea is 4 mg administered as either a single dose once daily or in divided doses twice daily. Because the incidence of hypoglycemia using AVANDIA 4 mg daily in combination with sulfonylurea is low, patients who are inadequately controlled on 4 mg/day of AVANDIA may benefit by cautious adjustment of the dose to 8 mg/day. The dose of AVANDIA may be increased at 8-12 weeks after initiation of therapy if there is insufficient reduction in FPG. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased.

If a dose of AVANDIA is missed with once a day dosing, the patient should be advised to take the dose as soon as they remember anytime during the day. If a dose is missed with twice a day dosing, the patient should be advised to take the missed dose as soon as they remember and the next dose at the usual time. Three doses should never be taken in one day to make up for a missed dose the day before. If a whole day of AVANDIA is missed, the usual dosing schedule should be followed the next day without making up for the missed doses.

Limited data are available with regard to overdosage in humans. In clinical studies in volunteers, AVANDIA has been administered at single oral doses of up to 20 mg and was well tolerated.

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status.

AVANDIA is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity in type 2 diabetes. Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control while reducing circulating insulin levels. It improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Rosiglitazone is not chemically or functionally related to the sulfonylureas, the biguanides or the alpha-glucosidase inhibitors. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator- activated receptor- gamma (PPARγ). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle and liver. Activation of PPARγ nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPARγ-responsive genes also participate in the regulation of fatty acid metabolism and in the maturation of preadipocytes, predominantly of subcutaneous origin.

Insulin resistance is a primary feature characterizing the pathogenesis of type 2 diabetes. AVANDIA results in increased responsiveness of insulin-dependent tissues and significantly improves hepatic and peripheral (muscle) tissue sensitivity to insulin in patients with type 2 diabetes. Clinical studies in patients with type 2 diabetes treated with AVANDIA either as monotherapy or in combination with metformin or sulfonylureas showed improved beta-cell function and decreased fasting plasma glucose, insulin and C-peptide values following 26 weeks of treatment. A homeostasis model assessment (HOMA) was conducted using fasting plasma glucose and insulin or C-peptide levels as a measure of insulin sensitivity and beta-cell function. In these studies, reductions in mean plasma pro-insulin and pro-insulin split product concentrations were also observed.

AVANDIA significantly reduced hemoglobin A1C (A1C, a marker for long term glycemic control), and fasting blood glucose (FBG) in patients with type 2 diabetes. Inadequately controlled hyperglycemia is associated with an increased risk of diabetic complications, including cardiovascular disorders and diabetic nephropathy, retinopathy and neuropathy.

Studies between 8 and 26 weeks with AVANDIA have shown a statistically significant reduction in markers of inflammation, C-reactive protein (CRP) and matrix metalloproteinase-9 (MMP-9). The clinical significance of these effects are still unknown. Further long term clinical trials are needed.

Estimates of LDL particle size can be determined by the LDL cholesterol (LDL) to apolipoprotein B (Apo B) ratio. In controlled clinical trials, rosiglitazone has been shown to increase the LDL cholesterol to Apo B ratio consistent with a beneficial change in LDL particle size from small dense LDL particles to larger more buoyant particles. This change has been confirmed by measuring LDL particle buoyancy (Rf) following 8 weeks treatment with rosiglitazone in an open-label study.

In clinical studies, treatment with AVANDIA resulted in an improvement in glycemic control, as measured by fasting plasma glucose (FPG) and hemoglobin A1C (A1C), with a concurrent reduction in insulin and C-peptide. Post-prandial glucose and insulin levels were also reduced. This is consistent with the mechanism of action of AVANDIA as an insulin sensitizer. The improvement in glycemic control was durable, with maintenance of effect for at least 52 weeks. In open-labelled extension studies sustained improvements in glycemic control (as measured by A1C levels) were observed in patients receiving rosiglitazone monotherapy for 36 months. The maximum recommended daily dose is 8 mg. Phase II studies indicated that no additional benefit was obtained with a total daily dose of 12 mg.

AVANDIA is believed to act primarily on muscle and adipose tissue whereas metformin acts primarily on the liver to decrease hepatic glucose output. The coadministration of AVANDIA with either metformin or sulfonylurea resulted in significantly improved glycemic control compared to any of these agents alone. These results are consistent with a synergistic effect on glycemic control when AVANDIA is used in combination therapy. In patients whose type 2 diabetes was inadequately controlled with metformin or sulfonylurea monotherapy, the addition of rosiglitazone led to reductions in A1C levels that were sustained for over 30 months of treatment, in open-labelled studies.

Weight gain observed in clinical studies with AVANDIA was associated with improved glycemic control (see Table 2). In addition, AVANDIA significantly decreased visceral (abdominal) fat stores while increasing subcutaneous abdominal fat. The reduction in visceral fat correlates with improved hepatic and peripheral tissue insulin sensitivity. Abdominal obesity is a risk factor for cardiovascular complications. Weight gain with thiazolidinediones can result from increases in subcutaneous adipose tissue and/or from fluid retention. Treatment should be re-evaluated in patients with excessive weight gain (see Warnings and Precautions and Adverse Reactions).

Table 2:

Weight Changes (kg) from Baseline During Clinical Trials with AVANDIA

Treatment Group	Duration	Control Group		AVANDIA 4 mg	AVANDIA 8 mg
			median (Range) [kg]	median (Range) [kg]	median (Range) [kg]
Monotherapy
AVANDIA	26 weeks	placebo	−0.9 (−9.6 to 6.8)	1.0 (−11.6 to 12.7)	3.1 (−6.8 to 13.9)
AVANDIA	52 weeks	sulfonylurea	2.0 (−11.5 to 12.2)	2.0 (−7.0 to 16.0)	2.6 (−11.0 to 22.0)
Combination Therapy
AVANDIA+sulfonylurea	26 weeks	sulfonylurea	0 (−6.0 to 14.0)	1.8 (−5.0 to 11.5)	—
AVANDIA+metformin	26 weeks	metformin	-1.4 (−7.7 to 5.9)	0.8 (−6.8 to 9.8)	2.1 (−5.4 to 13.1)

Patients with lipid abnormalities were not excluded from clinical trials of AVANDIA. In all 26-week controlled trials, across the recommended dose range, AVANDIA as monotherapy was associated with increases in total cholesterol, LDL, and HDL and decreases in free fatty acids. These changes were statistically significantly different from placebo or glyburide controls ( Table 3).

Increases in LDL occurred primarily during the first 1 to 2 months of therapy with AVANDIA and LDL levels remained stable, but elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL ratio peaked after 2 months of therapy and then appeared to decrease over time. Because of the temporal nature of lipid changes, the 52-week glyburide-controlled study is most pertinent to assess long-term effects on lipids. At baseline, week 26, and week 52, median LDL/HDL ratios were 3.0, 2.9, and 2.8, respectively for AVANDIA 4 mg twice daily and the median total cholesterol/HDL ratios were 4.76, 4.52 and 4.35, respectively. The corresponding values for glyburide were 3.2, 2.9, and 2.7 for the median LDL/HDL ratios and 4.90, 4.61 and 4.36 for the median total cholesterol/HDL ratios.

The pattern of LDL and HDL changes following therapy with AVANDIA in combination with sulfonylurea or metformin were generally similar to those seen with AVANDIA in monotherapy.

The changes in triglycerides during therapy with AVANDIA were variable and were generally not statistically different from placebo or glyburide controls.

Table 3: AVANDIA

Summary of Lipid Changes in 26-Week Placebo-controlled and 26-Week/52-Week Glyburide-controlled Monotherapy Studies

	Placebo-controlled Studies Week 26			Glyburide-controlled Study Week 26 and Week 52
	Placebo	AVANDIA		Glyburide Titration		AVANDIA 8 mg
		4 mg daily	8 mg daily	wk 26	wk 52	wk 26	wk 52
Free Fatty Acids (mmol/L)
N	207	428	436	181	168	166	145
Baseline (median)	0.61	0.58	0.61	0.92	0.92	0.93	0.93
% change from baseline (median)	−4.0	−15.6	−23.5	−5.5	−9.7	−26.7	−24.7
LDL-cholesterol (mmol/L)
N	190	400	374	175	160	161	133
Baseline (median)	3.15	3.26	3.19	3.68	3.55	3.62	3.62
% change from baseline (median)	+2.5	+10.3	+14.8	−3.7	−3.3	+7.1	+7.3
HDL-cholesterol (mmol/L)
N	208	429	436	184	170	170	145
Baseline (median)	1.06	1.14	1.09	1.17	1.18	1.19	1.19
% change from baseline (median)	+8.2	+10.3	+11.3	+4.7	+8.0	+13.2	+17.4

The long term significance of the lipid changes is not known.

Because AVANDIA does not stimulate insulin secretion, hypoglycemia is not expected to occur when AVANDIA is prescribed as monotherapy. Patients receiving AVANDIA in combination with other hypoglycemic agents (e.g. insulin secreting agents) may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary. As insulin sensitizers can only work in the presence of insulin, AVANDIA should not be used in patients with type 1 diabetes.

Maximum plasma concentration (C_max) and the area under the curve (AUC_0-inf) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range (see Table 4). The elimination half-life is 3 to 4 hours and is independent of dose.

Table 4: AVANDIA

Mean (SD) Pharmacokinetic Parameters for Rosiglitazone Following Single Oral Doses (n=32)

Parameter	1 mg Fasting	2 mg Fasting	8 mg Fasting	8 mg Fed
AUC0-inf [ng·h/mL]	358 (112)	733 (184)	2971 (730)	2890 (795)
Cmax [ng/mL]	76 (13)	156 (42)	598 (117)	432 (92)
Tmax [h]a	0.5 (0.5–1.5)	1.0 (0.5–2.0)	1.0 (0.5–1.5)	2.0 (1.0–5.0)
Half-life [h]	3.16 (0.72)	3.15 (0.39)	3.37 (0.63)	3.59 (0.70)
CL/Fb [L/h]	3.03 (0.87)	2.89 (0.71)	2.85 (0.69)	2.97 (0.81)

^a. T_max presented as median (range).
^b. CL/F=Oral Clearance.

Rosiglitazone is rapidly and completely absorbed after oral administration with negligible first-pass metabolism. The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed by 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC) but there was a decrease in the C_max (about 28%) and a delay in T_max of 1.75 hours. These changes are not likely to be clinically significant and AVANDIA may be administered with or without food.

The mean (SD) volume of dist