rosiglitazone maleate and metformin hydrochloride
Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION
Rosiglitazone maleate: CONGESTIVE HEART FAILURE AND MYOCARDIAL INFARCTION
- Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.2)]. After initiation of Avandamet, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of Avandamet must be considered.
- Avandamet is not recommended in patients with symptomatic heart failure. Initiation of Avandamet in patients with established NYHA Class III or IV heart failure is contraindicated. [See Contraindications (4) and Warnings and Precautions (5.2).]
- A meta-analysis of 52 clinical trials (mean duration 6 months; 16,995 total patients), most of which compared rosiglitazone to placebo, showed rosiglitazone to be associated with an increased risk of myocardial infarction. Three other trials (mean duration 46 months; 14,067 total patients), comparing rosiglitazone to some other approved oral antidiabetic agents or placebo, showed a statistically non-significant increased risk of myocardial infarction, and a statistically non-significant decreased risk of death. There have been no clinical trials directly comparing cardiovascular risk of rosiglitazone and ACTOS® (pioglitazone, another thiazolidinedione), but in a separate trial, pioglitazone (when compared to placebo) did not show an increased risk of myocardial infarction or death. [See Warnings and Precautions (5.3).]
- Because of the potential increased risk of myocardial infarction, Avandamet is available only through a restricted distribution program called the AVANDIA-Rosiglitazone Medicines Access Program. Both prescribers and patients need to enroll in the program. To enroll, call 1-800-AVANDIA or visit www.AVANDIA.com. [See Warnings and Precautions (5.4).]
Metformin hydrochloride: LACTIC ACIDOSIS
- Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure. [See Warnings and Precautions (5.1).]
- Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate. [See Warnings and Precautions (5.1).]
- If acidosis is suspected, discontinue Avandamet and hospitalize the patient immediately [see Warnings and Precautions (5.1)].
Indications and Usage for Avandamet
After consultation with a healthcare professional who has considered and advised the patient of the risks and benefits of rosiglitazone, Avandamet® is indicated as an adjunct to diet and exercise to improve glycemic control when treatment with both rosiglitazone and metformin is appropriate in adults with type 2 diabetes mellitus who either are:
- already taking rosiglitazone, or
- not already taking rosiglitazone and unable to achieve glycemic control on other diabetes medications and, in consultation with their healthcare provider, have decided not to take pioglitazone (ACTOS®) or pioglitazone-containing products (ACTOPLUS MET®, ACTOPLUS MET XR®, DUETACT®) for medical reasons.
- Other Important Limitations of Use:
- Due to its mechanism of action, rosiglitazone is active only in the presence of endogenous insulin. Therefore, Avandamet should not be used in patients with type 1 diabetes.
- Coadministration of Avandamet with insulin is not recommended [see Warnings and Precautions (5.2, 5.3)].
Avandamet Dosage and Administration
Prior to prescribing Avandamet, refer to Indications and Usage (1) for appropriate patient selection. Only prescribers enrolled in the AVANDIA-Rosiglitazone Medicines Access Program can prescribe Avandamet [see Warnings and Precautions (5.4)].
Starting Dose
Avandamet is generally given in divided doses with meals.
All patients should start the rosiglitazone component of Avandamet at the lowest recommended dose. Further increases in the dose of rosiglitazone should be accompanied by careful monitoring for adverse events related to fluid retention [see Boxed Warning and Warnings and Precautions (5.5)].
If therapy with a combination tablet containing rosiglitazone and metformin is considered appropriate for a patient with type 2 diabetes mellitus, then the selection of the dose of Avandamet should be based on the patient’s current doses of rosiglitazone and/or metformin.
To switch to Avandamet for patients currently treated with metformin, the usual starting dose of Avandamet is 4 mg rosiglitazone (total daily dose) plus the dose of metformin already being taken (see Table 1).
To switch to Avandamet for patients currently treated with rosiglitazone, the usual starting dose of Avandamet is 1,000 mg metformin (total daily dose) plus the dose of rosiglitazone already being taken (see Table 1).
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.
| PRIOR THERAPY | Usual Avandamet Starting Dose | |
| Total daily dose | Tablet strength | Number of tablets |
| Metformina | ||
| 1,000 mg/day | 2 mg/500 mg | 1 tablet twice a day |
| 2,000 mg/day | 2 mg/1,000 mg | 1 tablet twice a day |
| Rosiglitazone | ||
| 4 mg/day | 2 mg/500 mg | 1 tablet twice a day |
| 8 mg/day | 4 mg/500 mg | 1 tablet twice a day |
aFor patients on doses of metformin between 1,000 and 2,000 mg/day, initiation of Avandamet requires individualization of therapy.
Dose Titration
Avandamet is generally given in divided doses with meals, with gradual dose escalation. This reduces gastrointestinal side effects (largely due to metformin) and permits determination of the minimum effective dose for the individual patient.
Sufficient time should be given to assess adequacy of therapeutic response. FPG should be used initially to determine the therapeutic response to Avandamet. 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.
After an increase in metformin dosage, dose titration is recommended if patients are not adequately controlled after 1 to 2 weeks. After an increase in rosiglitazone dosage, dose titration is recommended if patients are not adequately controlled after 8 to 12 weeks.
Maximum Dose
The maximum recommended total daily dose of Avandamet is 8 mg rosiglitazone (taken as 4 mg twice daily) and 2,000 mg metformin (taken as 1,000 mg twice daily).
Specific Patient Populations
Renal Impairment: 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 (5.1)].
Hepatic Impairment: Liver enzymes should be measured prior to initiating treatment with Avandamet. Therapy with Avandamet should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT >2.5X upper limit of normal at start of therapy). After initiation of Avandamet, liver enzymes should be monitored periodically per the clinical judgment of the healthcare professional [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)].
Geriatric: 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.
Pediatric: Safety and effectiveness of Avandamet in pediatric patients have not been established. Avandamet and rosiglitazone are not recommended for use in pediatric patients.
Pregnancy: Avandamet is not recommended for use in pregnancy.
Dosage Forms and Strengths
Each film-coated oval tablet contains rosiglitazone as the maleate and metformin hydrochloride as follows:
- 2 mg/500 mg – pale pink, debossed with gsk on one side and 2/500 on the other
- 4 mg/500 mg – orange, debossed with gsk on one side and 4/500 on the other
- 2 mg/1,000 mg – yellow, debossed with gsk on one side and 2/1000 on the other
- 4 mg/1,000 mg – pink, debossed with gsk on one side and 4/1000 on the other
Contraindications
- Initiation in patients with established New York Heart Association (NYHA) Class III or IV heart failure [see Boxed Warning].
- Use in patients with renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions (5.1)].
- Use in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
- Use in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. Avandamet should be temporarily discontinued in these patients. [See Warnings and Precautions (5.1).]
Warnings and Precautions
Lactic Acidosis
Incidence and Management: Lactic acidosis is a rare, but serious, metabolic complication that can occur 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 mcg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases/1,000 patient years of exposure, with approximately 0.015 fatal cases/1,000 patient years of exposure). 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. 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 particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Treatment with Avandamet should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. 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. In addition, Avandamet should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.
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. 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 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 Contraindications (4)].
Factors That May Predispose Patients to Lactic Acidosis: Assessment of Renal Function: 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. In patients with advanced age, Avandamet should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. [See Dosage and Administration (2.4) and Use in Specific Populations (8.5).]
Before initiation of therapy with Avandamet and at least annually thereafter, renal function should be assessed and verified as normal. 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.
Medications That Affect Renal Function: 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 (7.2) and Clinical Pharmacology (12.4)], should be used with caution.
Hypoxic States: 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.
Radiologic Studies With Intravascular Iodinated Contrast Materials: Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin [see Contraindications (4)]. Therefore, in patients in whom any such study is planned, Avandamet should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
Surgical Procedures: Use of Avandamet should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Avandamet.
Change in Clinical Status of Patients With Previously Controlled Diabetes: A patient with type 2 diabetes 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 other appropriate corrective measures initiated.
[See also Warnings and Precautions (5.7).]
Cardiac Failure
Rosiglitazone, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone must be considered [see Boxed Warning].
Patients with congestive heart failure (CHF) NYHA Class I and II treated with rosiglitazone have an increased risk of cardiovascular events. A 52-week, double-blind, placebo-controlled echocardiographic trial was conducted in 224 patients with type 2 diabetes mellitus and NYHA Class I or II CHF (ejection fraction ≤45%) on background antidiabetic and CHF therapy. An independent committee conducted a blinded evaluation of fluid-related events (including congestive heart failure) and cardiovascular hospitalizations according to predefined criteria (adjudication). Separate from the adjudication, other cardiovascular adverse events were reported by investigators. Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed with rosiglitazone treatment compared to placebo during the 52-week trial. (See Table 2.)
| Events | Rosiglitazone | Placebo |
N = 110 n (%) | N = 114 n (%) | |
| Adjudicated | ||
| Cardiovascular deaths | 5 (5%) | 4 (4%) |
| CHF worsening | 7 (6%) | 4 (4%) |
| – with overnight hospitalization | 5 (5%) | 4 (4%) |
| – without overnight hospitalization | 2 (2%) | 0 (0%) |
| New or worsening edema | 28 (25%) | 10 (9%) |
| New or worsening dyspnea | 29 (26%) | 19 (17%) |
| Increases in CHF medication | 36 (33%) | 20 (18%) |
| Cardiovascular hospitalizationa | 21 (19%) | 15 (13%) |
| Investigator-reported, non-adjudicated | ||
| Ischemic adverse events | 10 (9%) | 5 (4%) |
| – Myocardial infarction | 5 (5%) | 2 (2%) |
| – Angina | 6 (5%) | 3 (3%) |
aIncludes hospitalization for any cardiovascular reason.
Initiation of Avandamet in patients with established NYHA Class III or IV heart failure is contraindicated. Avandamet is not recommended in patients with symptomatic heart failure. [See Boxed Warning.]
Patients experiencing acute coronary syndromes have not been studied in controlled clinical trials. In view of the potential for development of heart failure in patients having an acute coronary event, initiation of Avandamet is not recommended for patients experiencing an acute coronary event, and discontinuation of Avandamet during this acute phase should be considered.
Patients with NYHA Class III and IV cardiac status (with or without CHF) have not been studied in controlled clinical trials. Avandamet is not recommended in patients with NYHA Class III and IV cardiac status.
Congestive Heart Failure During Coadministration of Rosiglitazone With Insulin:In trials in which rosiglitazone was added to insulin, rosiglitazone increased the risk of congestive heart failure. Coadministration of rosiglitazone and insulin is not recommended. [See Indications and Usage (1) and Warnings and Precautions (5.3).]
In 7 controlled, randomized, double-blind trials which had durations from 16 to 26 weeks and which were included in a meta-analysis1[seeWarnings and Precautions (5.3)], patients with type 2 diabetes mellitus were randomized to coadministration of rosiglitazone and insulin (N = 1,018) or insulin (N = 815). In these 7 trials, rosiglitazone was added to insulin. These trials included patients with long-standing diabetes (median duration of 12 years) and a high prevalence of pre-existing medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. The total number of patients with emergent congestive heart failure was 23 (2.3%) and 8 (1.0%) in the rosiglitazone plus insulin and insulin groups, respectively.
Heart Failure in Observational Studies of Elderly Diabetic Patients Comparing Rosiglitazone to Pioglitazone: Three observational studies2-4 in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of hospitalized heart failure compared to use of pioglitazone. One other observational study5 in patients with a mean age of 54 years, which also included an analysis in a subpopulation of patients >65 years of age, found no statistically significant increase in emergency department visits or hospitalization for heart failure in patients treated with rosiglitazone compared to pioglitazone in the older subgroup.
Major Adverse Cardiovascular Events
Cardiovascular adverse events have been evaluated in a meta-analysis of 52 clinical trials, in long-term, prospective, randomized, controlled trials, and in observational studies.
Meta-Analysis of Major Adverse Cardiovascular Events in a Group of 52 Clinical Trials: A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 52 double-blind, randomized, controlled clinical trials (mean duration 6 months).1 These trials had been conducted to assess glucose-lowering efficacy in type 2 diabetes. Prospectively planned adjudication of cardiovascular events did not occur in most of the trials. Some trials were placebo-controlled and some used active oral antidiabetic drugs as controls. Placebo-controlled trials included monotherapy trials (monotherapy with rosiglitazone versus placebo monotherapy) and add-on trials (rosiglitazone or placebo, added to sulfonylurea, metformin, or insulin). Active control trials included monotherapy trials (monotherapy with rosiglitazone versus sulfonylurea or metformin monotherapy) and add-on trials (rosiglitazone plus sulfonylurea or rosiglitazone plus metformin, versus sulfonylurea plus metformin). A total of 16,995 patients were included (10,039 in treatment groups containing rosiglitazone, 6,956 in comparator groups), with 5,167 patient-years of exposure to rosiglitazone and 3,637 patient-years of exposure to comparator. Cardiovascular events occurred more frequently for patients who received rosiglitazone than for patients who received comparators (see Table 3).
| Eventa | Rosiglitazone (N=10,039) n (%) | Comparator (N=6,956) n (%) |
| MACE (a composite of myocardial infarction, cardiovascular death, or stroke) | 70 (0.7) | 39 (0.6) |
| Myocardial Infarction | 45 (0.4) | 20 (0.3) |
| Cardiovascular Death | 17 (0.2) | 9 (0.1) |
| Stroke | 18 (0.2) | 16 (0.2) |
| All-cause Death | 29 (0.3) | 17 (0.2) |
a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).
In this analysis, a statistically significant increased risk of myocardial infarction with rosiglitazone versus pooled comparators was observed. Analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, stroke, and cardiovascular death), referred to hereafter as MACE. Rosiglitazone had a statistically non-significant increased risk of MACE compared to the pooled comparators. A statistically significant increased risk of myocardial infarction and statistically non-significant increased risk of MACE with rosiglitazone was observed in the placebo-controlled trials. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE. (See Figure 1 and Table 4.)
Figure 1. Forest Plot of Odds Ratios (95% Confidence Intervals) for MACE and Myocardial Infarction in the Meta-Analysis of 52 Clinical Trials
| MACE | Myocardial Infarction | |||||
| N | n (%) | OR (95%CI) | n (%) | OR (95%CI) | ||
Active- Controlled Trials | RSG | 2,119 | 16 (0.8%) | 1.05 | 10 (0.5%) | 1.00 |
| Control | 1,918 | 14 (0.7%) | (0.48, 2.34) | 9 (0.5%) | (0.36, 2.82) | |
Placebo- Controlled Trials | RSG | 8,124 | 54 (0.7%) | 1.53 | 35 (0.4%) | 2.23 |
| Placebo | 5,636 | 28 (0.5%) | (0.94, 2.54) | 13 (0.2%) | (1.14, 4.64) | |
Overall | RSG | 10,039 | 70 (0.7%) | 1.44 | 45 (0.4%) | 1.8 |
| Control | 6,956 | 39 (0.6%) | (0.95, 2.20) | 20 (0.3%) | (1.03, 3.25) | |
RSG = rosiglitazone
Of the placebo-controlled trials in the meta-analysis, 7 trials had patients randomized to rosiglitazone plus insulin or insulin. There were more patients in the rosiglitazone plus insulin group compared to the insulin group with myocardial infarctions, MACE, cardiovascular deaths, and all-cause deaths (see Table 5). The total number of patients with stroke was 5 (0.5%) and 4 (0.5%) in the rosiglitazone plus insulin and insulin groups, respectively. The use of rosiglitazone in combination with insulin may increase the risk of myocardial infarction [See Warnings and Precautions (5.1).]
Eventa | Rosiglitazone (N=1,018) (%) | Insulin (N = 815) (%) |
OR (95% CI) |
| MACE (a composite of myocardial infarction, cardiovascular death, or stroke) | 1.3 | 0.6 | 2.14 (0.70, 7.83) |
| Myocardial infarction | 0.6 | 0.1 | 5.6 (0.67, 262.7) |
| Cardiovascular death | 0.4 | 0.0 | ND, (0.47, ∞) |
| All-cause death | 0.6 | 0.2 | 2.19 (0.38, 22.61) |
ND = not defined
a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).
Myocardial Infarction Events in Large, Long-Term, Prospective, Randomized, Controlled Trials of Rosiglitazone: Data from 3 large, long-term, prospective, randomized, controlled clinical trials of rosiglitazone were assessed separately from the meta-analysis.6-8 These 3 trials included a total of 14,067 patients (treatment groups containing rosiglitazone N = 6,311; comparator groups N = 7,756), with patient-year exposure of 24,534 patient-years for rosiglitazone and 28,882 patient-years for comparator. Patient populations in the trials included patients with impaired glucose tolerance, patients with type 2 diabetes who were initiating oral agent monotherapy, and patients with type 2 diabetes who had failed monotherapy and were initiating dual oral agent therapy. Duration of follow-up exceeded 3 years in each trial.
In each of these trials, there was a statistically non-significant increase in the risk of myocardial infarction for rosiglitazone versus comparator medications.
In a long-term, randomized, placebo-controlled, 2x2 factorial trial intended to evaluate rosiglitazone, and separately ramipril (an angiotensin converting enzyme inhibitor [ACEI]), on progression to overt diabetes in 5,269 subjects with glucose intolerance, the incidence of myocardial infarction was higher in the subset of subjects who received rosiglitazone in combination with ramipril than among subjects who received ramipril alone but not in the subset of subjects who received rosiglitazone alone compared to placebo.6 The higher incidence of myocardial infarction among subjects who received rosiglitazone in combination with ramipril was not confirmed in the two other large (total N = 8,798) long-term, randomized, active-controlled clinical trials conducted in patients with type 2 diabetes, in which 30% and 40% of patients in the two trials reported angiotensin-converting enzyme inhibitor use at baseline.7,8
There have been no adequately designed clinical trials directly comparing rosiglitazone to pioglitazone on cardiovascular risks. However, in a long-term, randomized, placebo-controlled cardiovascular outcomes trial comparing pioglitazone to placebo in patients with type 2 diabetes mellitus and prior macrovascular disease, pioglitazone was not associated with an increased risk of myocardial infarction or total mortality.9
The increased risk of myocardial infarction observed in the meta-analysis and large, long-term controlled clinical trials, and the increased risk of MACE observed in the meta-analysis described above, have not translated into a consistent finding of excess mortality from controlled clinical trials or observational studies. Clinical trials have not shown any difference between rosiglitazone and comparator medications in overall mortality or CV-related mortality.
Mortality in Observational Studies of Rosiglitazone Compared to Pioglitazone: Three observational studies in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of all-cause mortality compared to use of pioglitazone.2-4 One observational study5 in patients with a mean age of 54 years found no difference in all-cause mortality between patients treated with rosiglitazone compared to pioglitazone and reported similar results in the subpopulation of patients >65 years of age. One additional small, prospective, observational study10 found no statistically significant differences for CV mortality and all-cause mortality in patients treated with rosiglitazone compared to pioglitazone.
5.4 Rosiglitazone REMS (Risk Evaluation and Mitigation Strategy) Program
Because of the potential increased risk of myocardial infarction, Avandamet is available only through a restricted distribution program called the AVANDIA-Rosiglitazone Medicines Access Program [see Indications and Usage (1)]. Both prescribers and patients must enroll in the program to be able to prescribe or receive Avandamet, respectively. Avandamet will be available only from specially certified pharmacies participating in the program. As part of the program, prescribers will be educated about the potential increased risk of myocardial infarction and the need to limit the use of Avandamet to eligible patients. Prescribers will need to discuss with patients the risks and benefits of taking Avandamet. To enroll, call 1-800-AVANDIA or visit www.AVANDIA.com.
Edema
Avandamet should be used with caution in patients with edema. In a clinical trial in healthy volunteers who received rosiglitazone 8 mg once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared to placebo. Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead t
No comments:
Post a Comment