Avandamet

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).

In 32 healthy women, rosiglitazone maleate (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 rosiglitazone 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 rosiglitazone 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 CYP 2C8 inhibitor, montelukast; or, with CYP2C8 substrate paclitaxel. 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.

Other drugs tend to produce hyperglycemia and may lead to a loss of blood sugar control. These include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, estrogen plus progestogen, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to patients receiving AVANDAMET, the patient should be closely observed to maintain adequate glycemic control.

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving AVANDAMET.

Coadministration of rosiglitazone (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 rosiglitazone had no clinically relevant effect on the steady-state pharmacokinetics of warfarin.

Repeat oral dosing of rosiglitazone (8 mg once daily) for 14 days did not alter the steady-state pharmacokinetics of digoxin (0.375 mg once daily) in healthy volunteers. However, metformin has the potential for interaction with digoxin (see Drug Interactions, Cationic Drugs).

Interactions with food have not been established.

Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) that are eliminated by renal tubular secretion, theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such an interaction has been observed between metformin and oral cimetidine in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies. These studies showed a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Therefore, careful patient monitoring and dose adjustment of AVANDAMET or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Interactions with laboratory tests have not been established.

Interactions with herbal products have not been established.

Rosiglitazone (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 rosiglitazone is unlikely to cause clinically important drug interactions with other drugs metabolized via CYP3A4.

Concurrent administration of rosiglitazone (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.

A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood C_max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C_max and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically.

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).

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin C_max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T_max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

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.

The management of antidiabetic therapy with AVANDAMET should be individualized on the basis of effectiveness and tolerability while not exceeding the maximum recommended daily dose of 8 mg rosiglitazone/2000 mg metformin.

Consistent with the dosing of metformin (i.e., in divided doses), AVANDAMET should be given in divided doses with meals, with gradual dose escalation. This reduces GI side effects (largely due to metformin) and permits determination of the minimum effective dose for the individual patient.

Sufficient time should be given after initiation of AVANDAMET therapy or any dose increase to assess adequacy of therapeutic response. Fasting plasma glucose (FPG) should be used to determine the therapeutic response to AVANDAMET. After an increase in metformin dosage, dose titration is recommended if patients are not adequately controlled after 1-2 weeks. After an increase in rosiglitazone dosage, dose titration is recommended if patients are not adequately controlled after 8-12 weeks.

Increases in the rosiglitazone component 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).

No studies have been performed specifically examining the safety and efficacy of AVANDAMET in patients previously treated with other oral hypoglycemic agents and switched to AVANDAMET. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

AVANDAMET is not recommended for use in pregnancy or for use in pediatric patients.

The initial and maintenance dosing of AVANDAMET should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of AVANDAMET. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly (see Warnings and Precautions).

Therapy with AVANDAMET 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). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with AVANDAMET and periodically thereafter. AVANDAMET is contraindicated in patients with serious hepatic impairment (see Contraindications, Warnings and Precautions, Hepatic).

If a dose of AVANDAMET is missed, the patient should be advised to take one 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 AVANDAMET is missed, the usual dosing schedule should be followed the next day without making up for the missed doses.

When switching from combination therapy of rosiglitazone plus metformin as separate tablets: the usual starting dose of AVANDAMET is the dose of rosiglitazone and metformin already being taken.

If additional glycemic control is needed: the daily dose of AVANDAMET may be increased by increments of 4 mg rosiglitazone and/or 500 mg metformin, up to the maximum recommended total daily dose of 8 mg/2000 mg.

In postmarketing experience with rosiglitazone, 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 rosiglitazone have been received rarely. These patients frequently reported concurrent peripheral edema. In some cases, symptoms improved following discontinuation of rosiglitazone (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 rosiglitazone.

In clinical trials, anemia and edema were generally dose-related, mild to moderate in severity and usually did not require discontinuation of treatment with rosiglitazone.

In clinical trials, edema was reported in 4.8% of patients taking rosiglitazone compared to 1.3% on placebo, and 2.2% on metformin monotherapy and 4.4% on rosiglitazone in combination with maximum doses of 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 rosiglitazone was used in combination with insulin (see Warnings And Precautions, General).

In double blind studies where rosiglitazone was administered for up to one year, serious adverse experiences of ischemic heart disease were reported in 1.3% of patients taking rosiglitazone maleate compared to 0.5% on placebo, 1.3% on metformin and 1.2% on rosiglitazone in combination with maximum doses of 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 rosiglitazone 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, Rosiglitazone maleate, 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 rosiglitazone containing regimens and 1.76 events per 100 person years for other antidiabetic agents [Hazard ratio 0.93 (95% confidence interval 0.80-1.10)].

In clinical trials, dose-related weight gain was seen with rosiglitazone alone and in combination with other hypoglycemic agents (see Action and Clinical Pharmacology and Warnings and Precautions).

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

In double blind studies, anemia was reported in 1.9% of patients taking rosiglitazone compared to 0.7% on placebo, and 2.2% on metformin and 7.1% on rosiglitazone in combination with maximum doses of metformin. Treatment was required for 0.3% of patients with an adverse event of anemia. These adverse experiences rarely led to withdrawal. 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 (see Adverse Reactions, Abnormal Hematologic and Clinical Chemistry Findings).

Constipation was commonly observed and generally mild to moderate in nature in clinical trials of rosiglitazone with metformin.

A long-term study (ADOPT) compared the use of rosiglitazone maleate (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 rosiglitazone maleate (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 rosiglitazone maleate were reported in the upper arm, hand, and foot (see Warnings and Precautions, Endocrine and Metabolism, Rosiglitazone maleate, Fractures). The observed incidence of fractures for male patients was similar among the 3 treatment groups.

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.

The incidence of rash/dermatitis in controlled clinical trials was comparable to placebo for metformin monotherapy.

Gastrointestinal symptoms (diarrhea, nausea, vomiting, abdominal bloating, flatulence, and anorexia) are the most common reactions to metformin and are approximately 30% more frequent in patients on metformin monotherapy than in placebo-treated patients, particularly during initiation of metformin therapy. These symptoms are generally transient and resolve spontaneously during continued treatment. Occasionally, temporary dose reduction may be useful.

Because gastrointestinal symptoms during therapy initiation appear to be dose-related, they may be decreased by gradual dose escalation and by having patients take AVANDAMET with meals (see Dosage and Administration).

During initiation of AVANDAMET therapy, approximately 3% of patients may complain of an unpleasant or metallic taste, which usually resolves spontaneously.

In clinical studies in 4598 patients treated with rosiglitazone 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 rosiglitazone had reversible elevations in ALT >3 times the upper limit of the reference range compared to 0.2% on placebo and 0.5% on active comparators. Hyperbilirubinemia was found in 0.3% of patients treated with rosiglitazone compared with 0.9% treated with placebo and 1% in patients treated with active comparators. Overall, there was a decrease in mean values for ALT, AST, alkaline phosphatase and bilirubin over time in patients treated with rosiglitazone (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 rosiglitazone, 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 clinical trials, reports of hypoglycemia in patients treated with rosiglitazone added to maximum metformin monotherapy were more frequent than in patients treated with rosiglitazone or metformin monotherapies. In double-blind studies, hypoglycemia was reported by 0.6% of patients receiving rosiglitazone as monotherapy compared to 0.2% on placebo and by 3.0% of patients receiving rosiglitazone in combination with maximum doses of metformin compared to 1.3% on metformin monotherapy.

Small decreases in hematological parameters were more common in the patients treated with rosiglitazone than in placebo-treated patients. Leukopenia was reported in 0.4% of rosiglitazone patients compared to 0.2% of patients on placebo, 0% on metformin and 0.3% on rosiglitazone in combination with maximum doses of metformin. Decreases may be related to increased plasma volume observed with treatment with rosiglitazone. The mean decrease in hemoglobin in patients treated with rosiglitazone was approximately 10 to 12 g/L; the decrease in hematocrit was 0.03 to 0.04.

During controlled clinical trials of 29 weeks duration, approximately 9% of patients on metformin monotherapy developed asymptomatic subnormal serum vitamin B₁₂ levels; serum folic acid levels did not decrease significantly. However, only five cases of megaloblastic anemia have been reported with metformin administration (none during U.S. clinical studies) and no increased incidence of neuropathy has been observed. Therefore, serum vitamin B₁₂ levels should be appropriately monitored or periodic parenteral B₁₂ supplementation considered (see Warnings and Precautions).

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

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

However, limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged and C_max is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. Metformin treatment and therefore treatment with AVANDAMET should not be initiated in patients 80 years of age or older unless measurement of creatinine clearance demonstrates that renal function is not reduced (see Warnings and Precautions and Dosage and Administration).

Each pale pink, film-coated, oval tablet, debossed with gsk on one side and 2/500 on the other, contains: rosiglitazone maleate equivalent to rosiglitazone 2 mg and metformin HCl 500 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone 29-32, sodium starch glycolate, titanium dioxide and one or more of the following: red and yellow iron oxides. Bottles of 100.

Each yellow, film-coated, oval tablet, debossed with gsk on one side and 1/500 on the other, contains: rosiglitazone maleate equivalent to rosiglitazone 1 mg and metformin HCl 500 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone 29-32, sodium starch glycolate, titanium dioxide and one or more of the following: red and yellow iron oxides. Bottles of 100.

Each yellow, film-coated, oval tablet, debossed with gsk on one side and 2/1000 on the other, contains: rosiglitazone maleate equivalent to rosiglitazone 2 mg and metformin HCl 1000 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone 29-32, sodium starch glycolate, titanium dioxide and one or more of the following: red and yellow iron oxides. Bottles of 100.

Each pink, film-coated, oval tablet, debossed with gsk on one side and 4/1000 on the other, contains: rosiglitazone maleate equivalent to rosiglitazone 4 mg and metformin HCl 1000 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone 29-32, sodium starch glycolate, titanium dioxide and one or more of the following: red and yellow iron oxides. Bottles of 100.

Each orange, film-coated, oval tablet, debossed with gsk on one side and 4/500 on the other, contains: rosiglitazone maleate equivalent to rosiglitazone 4 mg and metformin HCl 500 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone 29-32, sodium starch glycolate, titanium dioxide and one or more of the following: red and yellow iron oxides. Bottles of 100.

As with other thiazolidinediones, rosiglitazone 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.

Since impaired hepatic function has been associated with some cases of lactic acidosis, AVANDAMET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Lactic acidosis is a rare, but serious, metabolic complication that occurs due to metformin accumulation during treatment with AVANDAMET; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. AVANDAMET treatment should not be initiated in patients 80 years of age or older, unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking AVANDAMET and by use of the minimum effective dose of AVANDAMET.

In addition, AVANDAMET should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, AVANDAMET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking AVANDAMET, since alcohol potentiates the effects of metformin on lactate metabolism.

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see General). AVANDAMET should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of AVANDAMET, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking AVANDAMET do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity or technical problems in sample handling. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking AVANDAMET, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery (see Cardiovascular, Renal, Hepatic, and Contraindications).

If acidosis of any kind develops, AVANDAMET should be discontinued immediately.

There are no controlled trials of AVANDAMET in pregnant women. Rosiglitazone has been reported to cross the human placenta and to be detectable in fetal tissues. AVANDAMET 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, rosiglitazone 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.

Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see Drug Interactions), should be used with caution.

Dose-related weight gain was seen with rosiglitazone 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).

Impairment of vitamin B₁₂ and folic acid absorption has been reported in some patients on metformin. Therefore, measurements of serum vitamin B₁₂ and folic acid are advisable at least every one to two years in patients on long-term treatment with AVANDAMET.

A decrease to subnormal levels of previously normal serum vitamin B₁₂ levels, without clinical manifestations, is observed in approximately 7% of patients receiving metformin hydrochloride in controlled clinical trials of 28 weeks duration. Such a decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on AVANDAMET and any apparent abnormalities should be appropriately investigated and managed (see Monitoring and Laboratory Tests). Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels.

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 rosiglitazone maleate (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 majoritiy of the fractures in the females who received rosiglitazone maleate 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 rosiglitazone maleate, and attention should be given to assessing and maintaining bone health according to current standards of care.

Thiazolidinediones, like rosiglitazone, 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 (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. AVANDAMET should be discontinued if any deterioration in cardiac status occurs.

AVANDAMET 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 AVANDAMET in patients experiencing an acute coronary event is not recommended. Furthermore, discontinuation of AVANDAMET during the acute phase should be considered.

There are no data on the use of AVANDAMET in patients under 18 years of age; therefore, AVANDAMET 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.

Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive AVANDAMET (see Endocrine and Metabolism, Geriatrics (≥65 years of age); and Dosage and Administration).

Before initiation of therapy with AVANDAMET and every 6 months while on AVANDAMET therapy, renal function should be assessed and verified as being within normal range. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and AVANDAMET discontinued if evidence of renal impairment is present.

Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with hypoglycemic agents (such as sulfonylureas) or ethanol. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

AVANDAMET should be used with caution in patients with edema. In healthy volunteers who received rosiglitazone 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 rosiglitazone, and may be dose related (see Adverse Reactions). For information on macular edema, see Warnings and Precautions, Ophthalmologic.

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

The use of AVANDAMET in combination with 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 dose adjustment of the rosiglitazone or metformin components may be needed when AVANDAMET is coadministered with CYP2C8 inhibitors or inducers or cationic drugs that are eliminated by renal tubular excretion (see Drug Interactions).

A diabetic patient previously well controlled on AVANDAMET who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate and metformin levels. If acidosis of either form occurs, AVANDAMET must be stopped immediately and appropriate corrective measures initiated (see Warnings and Precautions, Lactic Acidosis).

When a patient stabilized on any diabetic 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 AVANDAMET and temporarily administer insulin. AVANDAMET may be reinstituted after the acute episode is resolved.

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 rosiglitazone 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 AVANDAMET 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 rosiglitazone.

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 rosiglitazone 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)].

Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients receiving AVANDAMET, the drug should be promptly discontinued.

The effect of AVANDAMET or its components on labour and delivery in humans is unknown.

Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, AVANDAMET should only be used in patients with normal renal function (see Contraindications and Warnings and Precautions). Because aging is associated with reduced renal function, AVANDAMET should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of AVANDAMET (see Warnings and Precautions and Dosage and Administration).

Use of AVANDAMET should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids). AVANDAMET should be discontinued 2 days before surgical intervention and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

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 AVANDAMET in all patients and periodically thereafter (see Warnings and Precautions, Hepatic).

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, vitamin B₁₂ deficiency should be excluded.

No studies have been conducted with the combined components of AVANDAMET. In studies performed with the individual components, both rosiglitazone-related material and metformin were detectable in milk from lactating rats. It is not known whether rosiglitazone and/or metformin is excreted in human milk. Because many drugs are excreted in human milk, AVANDAMET should not be administered to a nursing woman. If AVANDAMET is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Administration of AVANDAMET 4 mg/500 mg with food resulted in no change in overall exposure (AUC) for either rosiglitazone or metformin. However, there were decreases in C_max of both components (22% for rosiglitazone and 15% for metformin, respectively) and a delay in T_max of both components (1.5 hrs for rosiglitazone and 0.5 hrs for metformin, respectively). These changes are not likely to be clinically significant. The pharmacokinetics of both the rosiglitazone component and the metformin component of AVANDAMET when taken with food were similar to the pharmacokinetics of rosiglitazone and metformin when administered concomitantly as separate tablets with food.

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. In rosiglitazone and metformin combination studies, efficacy was demonstrated with no gender differences in glycemic response.

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females.

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

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 AVANDAMET 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).

No pharmacokinetic studies have been conducted in subjects with hepatic insufficiency with metformin.

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.

However, limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged and C_max is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. Metformin treatment and therefore treatment with AVANDAMET should not be initiated in patients 80 years of age or older unless measurement of creatinine clearance demonstrates that renal function is not reduced (see Warnings and Precautions and Dosage and Administration).

AVANDAMET tablets combine two antidiabetic agents with different but complementary mechanisms of action to improve glycemic control while reducing circulating insulin levels in patients with type 2 diabetes: rosiglitazone maleate, a member of the thiazolidinedione class and metformin hydrochloride, a member of the biguanide class. Thiazolidinediones are insulin sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.

Rosiglitazone maleate 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. Rosiglitazone maleate 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 rosiglitazone either as monotherapy or in combination with metformin 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.

Rosiglitazone 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 rosiglitazone 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.

Metformin hydrochloride is an antihyperglycemic agent, which improves glucose tolerance in type 2 diabetes subjects, lowering both basal and postprandial plasma glucose. Metformin is not chemically or pharmacologically related to the oral sulfonylureas, thiazolidinediones, or alpha-glucosidase inhibitors. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see Warnings and Precautions) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

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

No studies of metformin hydrochloride pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51) and Hispanics (n=24).

Patients with lipid abnormalities were not excluded from clinical trials of rosiglitazone. In all 26-week controlled trials, across the recommended dose range, rosiglitazone 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 controls.

Increases in LDL occurred primarily during the first 1 to 2 months of therapy with rosiglitazone 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. The pattern of LDL and HDL changes following therapy with rosiglitazone in combination with metformin was generally similar to those seen with rosiglitazone in monotherapy.

The changes in triglycerides during therapy with rosiglitazone were variable and were generally not statistically different from controls.

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

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.

In subjects with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Warnings and Precautions).

Since metformin is contraindicated in patients with renal impairment, administration of AVANDAMET is contraindicated in these patients.