Avandia

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).

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.

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.

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 (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.

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.

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.

Interactions with food have not been established.

Interactions with laboratory tests have not been established.

Interactions with herbal products have not been established.

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.

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 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).

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.

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.

Single oral doses of glimepiride in 14 healthy adult subjects had no clinically significant effect on the steady-state pharmacokinetics of AVANDIA. No clinically significant reductions in glimepiride AUC and C_max were observed after repeat doses of AVANDIA for 8 days in healthy adult subjects.

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.

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.

The management of antidiabetic therapy should be individualized.

Increases in rosiglitazone to 8 mg/day should be undertaken cautiously following appropriate clinical evaluation to assess the patient’s risk of developing adverse reactions relating to fluid retention (see Warnings and Precautions and Adverse Reactions). The dose of AVANDIA used in combination with a sulfonylurea should not exceed 4 mg daily (see Recommended Dose and Dosage Adjustment, Combination Therapy with Sulfonylurea).

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). AVANDIA is contraindicated in patients with serious hepatic impairment. See Contraindications, Warnings and Precautions, Hepatic and Action and Clinical Pharmacology, Special Populations and Conditions, Hepatic Insufficiency.

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 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. The dose of AVANDIA used in combination with a sulfonylurea should not exceed 4 mg daily. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased (see Warnings and Precautions and Adverse Reactions).

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.

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.

In a 4 to 6 year monotherapy study (ADOPT), adverse reactions observed with AVANDIA were generally consistent to those observed in shorter-term trials as presented in Table 1, above). However, fractures were reported in a greater number of females with AVANDIA compared to glyburide or metformin (see Warnings and Precautions, Endocrine and Metabolism, Fractures and Adverse Reactions, Adverse Drug Reaction Overview).

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).

Reports of events related to cardiovascular ischemia including myocardial infarction, and hypertension or hypertension accelerated have been received.

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).

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

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.

Postmarketing reports of parotid gland enlargement have been associated with rosiglitazone and approximately one third of the reports resolved or improved following discontinuation of AVANDIA.

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, 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 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 or insulin (see Warnings and Precautions, General and Cardiovascular).

In clinical trials, an increased incidence of heart failure has also been observed when AVANDIA was added to a sulfonylurea (see Warnings and Precautions, Cardiovascular).

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 a retrospective analysis of data from pooled clinical studies, which included patients on combination therapy with insulin as well as patients with NYHA Class I and II heart failure, the overall incidence of events typically associated with cardiac ischemia was higher for AVANDIA containing regimens, 2.00% versus comparators, 1.53% [Hazard ratio 1.30 (95% confidence interval 1.004-1.69)]. In a subgroup analysis of this data, this risk was further increased in patients receiving nitrates with approximately twice as many events in patients receiving rosiglitazone versus comparators (see Warnings and Precautions, Cardiovascular, Ischemic Heart Disease). In a large observational study where patients were well-matched at baseline, the incidence of the composite endpoint of myocardial infarction and coronary revascularization was 1.75 events per 100 person years for AVANDIA containing regimens and 1.76 events per 100 person years for other anti-diabetic agents [Hazard ratio 0.93 (95% confidence interval 0.80-1.10)].

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). In a long-term monotherapy trial (ADOPT) in drug-naïve patients, median weight change (range) at 4 years was 3.5 kg (−31.0 to 41.3) for AVANDIA, 2.0 kg (−28.6 to 24.9) for glyburide, and −2.4 kg (−46.0 to 12.9) for metformin. This weight change with AVANDIA occurred consistently over the duration of the study.

A long-term study (ADOPT) compared the use of AVANDIA (n=1456), glyburide (n=1441), and metformin (n=1454) as monotherapy in type 2 diabetes patients followed up to 6 years. Fractures were reported in a greater number of females with AVANDIA (9.3%, 2.7/100 patient-years) compared to glyburide (3.5%, 1.3/100 patient-years) or metformin (5.1%, 1.5/100 patient-years). The majority of the fractures in the females who received AVANDIA were reported in the upper arm, hand, and foot (see Warnings and Precautions, Endocrine and Metabolism, Fractures). The observed incidence of fractures for male patients was similar among the 3 treatment groups.

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 either agent may be necessary.

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.

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.

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.

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 increases in total cholesterol and LDL have been observed following treatment with AVANDIA (see Table 3, Action and Clinical Pharmacology, Pharmacodynamics and Clinical Effects).

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.

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.

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.

Each red-brown, pentagonal film-coated TILTAB tablet, debossed with SB or GSK on one side and “8” on the other, contains: rosiglitazone maleate equivalent to rosiglitazone 8 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch glycolate, titanium dioxide and triacetin; colorant: one or more of the following: synthetic red and yellow iron oxides and talc. Bottles of 60.

Each orange, pentagonal film-coated TILTAB tablet, debossed with SB or GSK on one side and “4” on the other, contains: rosiglitazone maleate equivalent to rosiglitazone 4 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch glycolate, titanium dioxide and triacetin; colorant: one or more of the following: synthetic red and yellow iron oxides and talc. Bottles of 100.

Each pink, pentagonal film-coated TILTAB tablet, debossed with SB or GSK on one side and “2” on the other, contains: rosiglitazone maleate equivalent to rosiglitazone 2 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch glycolate, titanium dioxide and triacetin; colorant: one or more of the following: synthetic red and yellow iron oxides and talc. Bottles of 60.

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.

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.

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).

In a retrospective analysis of data from pooled clinical studies, which included patients on combination therapy with insulin as well as patients with NYHA Class I and II heart failure, the overall incidence of events typically associated with cardiac ischemia was higher for AVANDIA containing regimens, 2.00% versus comparators, 1.53% [Hazard ratio 1.30 (95% confidence interval 1.004-1.69)]. In a subgroup analysis of this data, this risk was further increased in patients receiving nitrates with approximately twice as many events in patients receiving rosiglitazone versus comparators. The use of AVANDIA is therefore not recommended for patients being treated with nitrates.

The completion of an adequately-designed cardiovascular outcome study is needed to further evaluate the risk of myocardial ischemic events associated with AVANDIA.

In a large observational study where patients were well-matched at baseline, the incidence of the composite endpoint of myocardial infarction and coronary revascularization was 1.75 events per 100 person years for AVANDIA containing regimens and 1.76 events per 100 person years for other anti-diabetic agents [Hazard ratio 0.93 (95% confidence interval 0.80-1.10)].

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

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

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.

Dose-related weight gain was seen with AVANDIA alone and in combination with other hypoglycemic agents. 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.

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.

For safety reasons, the use of AVANDIA in combination with insulin is not indicated.

The use of AVANDIA in combination with metformin and a sulfonylurea (triple therapy) is not indicated. An increase in reporting of fluid retention related events (including congestive heart failure) has been seen in patients receiving rosiglitazone in combination with metformin and a sulfonylurea.

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

In a 4 to 6 year comparative study (ADOPT) of glycemic control with monotherapy in recently diagnosed patients with Type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking AVANDIA (9.3%, 2.7 patients per 100 patient-years) versus glyburide (3.5%, 1.3 patients per 100 patient-years) or metformin (5.1%, 1.5 patients per 100 patient-years). The majority of the fractures in the females who received AVANDIA were reported in the upper arm, hand, and foot (see Adverse Reactions). The risk of fracture should be considered in the care of patients, especially female patients, treated with AVANDIA, and attention should be given to assessing and maintaining bone health according to current standards of care.

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).

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) should be closely monitored. (See Adverse Reactions.) An increase in reporting of fluid retention related events including congestive heart failure has been seen in patients receiving rosiglitazone in combination with metformin and a sulfonylurea. This triple therapy regimen is not an approved indication.

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.

AVANDIA is contraindicated in patients with NYHA Class I, II, III and IV heart failure. Patients with severe heart failure (including NYHA Class III and IV cardiac status) were not studied during the clinical trials.

Patients experiencing acute coronary syndromes (ACS) have not been studied in rosiglitazone controlled clinical trials. Since patients experiencing ACS are at an increased risk of developing heart failure, and in view of the potential for rosiglitazone to cause or exacerbate heart failure, initiation of AVANDIA in patients experiencing an acute coronary event is not recommended. Furthermore, discontinuation of AVANDIA during the acute phase should be considered.

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.

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 either agent may be necessary.

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.

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.

Therapy with AVANDIA should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5 times the upper limit of normal).

Rare cases of severe hepatocellular injury have been reported with thiazolidinediones.

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 (see Adverse Reactions, Post-Market Adverse Drug Reactions).

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.

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 (ALT levels ≤2.5 times the upper limit of normal) 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.

The mean (SD) volume of distribution (Vss) of rosiglitazone after intravenous administration to healthy subjects is approximately 14.1 (3.1) L. Rosiglitazone is approximately 99.8% bound to plasma proteins, primarily albumin.

Population pharmacokinetic analyses from three Phase III trials including 642 men and 405 women with type 2 diabetes (aged 35 to 80 years) showed that the pharmacokinetics of rosiglitazone are not influenced by age, race, smoking, or alcohol consumption. Both oral clearance (CL/F) and oral steady-state volume of distribution (Vss/F) were shown to increase with increases in body weight. Over the weight range observed in these analyses (50 to 150 kg), the range of predicted CL/F and Vss/F values varied by <1.7-fold and 2.3-fold, respectively. Additionally, rosiglitazone CL/F was shown to be lower (about 6%) in female patients compared to males of the same body weight. The population mean CL/F of rosiglitazone for a typical male weighing 84 kg was 2.48 L/h. The Vss/F in an 84 kg patient was 17.9L. The inter-patient variability in CL/F and Vss/F were 31% and 23%, respectively.

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.

Following oral or intravenous administration of [¹⁴C] rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively. The plasma half-life of [¹⁴C] related material ranged from 103 to 158 hours.

Results of the population pharmacokinetic analysis showed that the mean oral clearance of rosiglitazone in female patients (n=405) was 15% lower compared to male patients (n=642), primarily related to lower body weight in females.

As monotherapy and in combination with metformin, AVANDIA improved glycemic control in both males and females. In metformin combination studies, efficacy was demonstrated with no gender differences in glycemic response.

In monotherapy studies, a greater therapeutic response was observed in females; however, in more obese patients, gender differences were less evident. For a given body mass index (BMI), females tend to have a greater fat mass than males. Since the molecular target PPARγ is expressed in adipose tissues, this differentiating characteristic may account, at least in part, for the greater response to AVANDIA in females. Since safety profiles were similar between male and female patients in clinical studies and, as therapy should be individualized, no dose adjustments are necessary based on gender.

Rosiglitazone is extensively metabolized with no unchanged drug excreted in the urine. The major routes of metabolism were N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than the parent drug and, therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone. In vitro data demonstrate that rosiglitazone is predominantly metabolized by Cytochrome P450 (CYP) isoenzyme 2C8, with CYP2C9 contributing as only a minor pathway.

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 promote the maturation of preadipocytes and have been associated with weight gain. Obesity is a major problem in adolescents with type 2 diabetes.

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.

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.

Unbound oral clearance of rosiglitazone was significantly lower in patients with moderate to severe liver disease (Child-Pugh Class B/C) compared to healthy subjects. As a result, unbound C_max and AUC_0-inf were increased 2- and 3-fold, respectively. Elimination half-life for rosiglitazone was about 2 hours longer in patients with liver disease, compared to healthy subjects. 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 baseline (see Warnings and Precautions, Hepatic).

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. In a 4 to 6 year monotherapy study in drug-naïve patients, rosiglitazone treated patients showed an improvement in insulin sensitivity. The initial improvement in beta-cell function observed with AVANDIA was not sustained and gradually declined after one year for the duration of the study but continued to remain above baseline, as was the case for metformin and glyburide. 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.

Results of a population pharmacokinetic analysis including subjects of Caucasian, black and other ethnic origins indicate that race has no influence on the pharmacokinetics of rosiglitazone.

There are no clinically relevant differences in the pharmacokinetics of rosiglitazone in patients with mild to severe renal impairment or in hemodialysis-dependent patients, compared to subjects with normal renal function. No dosage adjustment is therefore required in such patients. Since metformin is contraindicated in patients with renal impairment, metformin in combination with AVANDIA is contraindicated in these patients.