Rosiglitazone Maleate and Glimepiride

The following adverse reactions are discussed in more detail elsewhere in the labeling:

• Cardiac Failure With Rosiglitazone [see WARNINGS AND PRECAUTIONS]
• Major Adverse Cardiovascular Events [see WARNINGS AND PRECAUTIONS]
• Hypoglycemia [see WARNINGS AND PRECAUTIONS]
• Edema [see WARNINGS AND PRECAUTIONS]
• Weight Gain [see WARNINGS AND PRECAUTIONS]
• Hepatic Effects [see WARNINGS AND PRECAUTIONS]
• Macular Edema [see WARNINGS AND PRECAUTIONS]
• Fractures [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
• Hematologic Effects [see WARNINGS AND PRECAUTIONS]
• Hemolytic Anemia [see WARNINGS AND PRECAUTIONS]
• Increased Risk of Cardiovascular Mortality for Sulfonylurea Drugs [see WARNINGS AND PRECAUTIONS]
• Ovulation [see WARNINGS AND PRECAUTIONS]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 3 summarizes adverse events occurring at a frequency of ≥ 5% in any treatment group in the 28-week, double-blind trial of AVANDARYL in patients with type 2 diabetes mellitus inadequately controlled on diet and exercise. Patients in this trial were started on AVANDARYL 4 mg/1 mg, rosiglitazone 4 mg, or glimepiride 1 mg. Doses could be increased at 4-week intervals to reach a maximum total daily dose of either 4 mg/4 mg or 8 mg/4 mg for AVANDARYL, 8 mg for rosiglitazone monotherapy, or 4 mg for glimepiride monotherapy.

Table 3: Adverse Events ( ≥ 5% in any Treatment Group) Reported by Patients With Inadequate Glycemic Control on Diet and Exercise in a 28-Week, Double-blind Clinical Trial of AVANDARYL

Hypoglycemia was reported to be generally mild to moderate in intensity and none of the reported events of hypoglycemia resulted in withdrawal from the trial. Hypoglycemia requiring parenteral treatment (i.e., intravenous glucose or glucagon injection) was observed in 3 (0.7%) patients treated with AVANDARYL.

Edema was reported by 3.2% of patients on AVANDARYL, 3.0% on rosiglitazone alone, and 2.3% on glimepiride alone.

Congestive heart failure was observed in 1 (0.2%) patient treated with AVANDARYL and in 1 (0.4%) patient treated with rosiglitazone monotherapy.

Trials utilizing rosiglitazone in combination with a sulfonylurea provide support for the use of AVANDARYL. Adverse event data from these trials, in addition to adverse events reported with the use of rosiglitazone and glimepiride therapy, are presented below.

Rosiglitazone: The most common adverse experiences with rosiglitazone monotherapy ( ≥ 5%) were upper respiratory tract infection, injury, and headache. Overall, the types of adverse experiences reported when rosiglitazone was added to a sulfonylurea were similar to those during monotherapy with rosiglitazone. In controlled combination therapy trials with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose-related, were reported. Few patients were withdrawn for hypoglycemia ( < 1%) and few episodes of hypoglycemia were considered to be severe ( < 1%).

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

Edema was reported by 4.8% of patients receiving rosiglitazone compared with 1.3% on placebo, and 1.0% on sulfonylurea monotherapy. The reporting rate of edema was higher for rosiglitazone 8 mg added to a sulfonylurea (12.4%) compared with other combinations, with the exception of insulin. Anemia was reported by 1.9% of patients receiving rosiglitazone compared with 0.7% on placebo, 0.6% on sulfonylurea monotherapy, and 2.3% on rosiglitazone in combination with a sulfonylurea. Overall, the types of adverse experiences reported when rosiglitazone was added to a sulfonylurea were similar to those during monotherapy with rosiglitazone.

In 26-week, double-blind, fixed-dose trials, edema was reported with higher frequency in the rosiglitazone plus insulin combination trials (insulin, 5.4%; and rosiglitazone in combination with insulin, 14.7%). Reports of new onset or exacerbation of congestive heart failure occurred at rates of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in combination with rosiglitazone [see BOXED WARNING, WARNINGS AND PRECAUTIONS].

Long-term Trial of Rosiglitazone as Monotherapy: A 4- to 6-year trial (ADOPT) compared the use of rosiglitazone (n = 1,456), glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients recently diagnosed with type 2 diabetes who were not previously treated with antidiabetic medication. Table 4 presents adverse reactions without regard to causality; rates are expressed per 100 patient-years (PY) exposure to account for the differences in exposure to trial medication across the 3 treatment groups.

In ADOPT, fractures were reported in a greater number of women treated with rosiglitazone (9.3%, 2.7/100 patient-years) compared with glyburide (3.5%, 1.3/100 patient-years) or metformin (5.1%, 1.5/100 patient-years). The majority of the fractures in the women who received rosiglitazone were reported in the upper arm, hand, and foot. [See WARNINGS AND PRECAUTIONS] The observed incidence of fractures for male patients was similar among the 3 treatment groups.

Table 4: On-therapy Adverse Events [ ≥ 5 Events/100 Patient-Years (PY)] in any Treatment Group Reported in a 4- to 6-Year Clinical Trial of Rosiglitazone as Monotherapy (ADOPT)

Long-term Trial of Rosiglitazone as Combination Therapy (RECORD): RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) was a multicenter, randomized, open-label, non-inferiority trial in subjects with type 2 diabetes inadequately controlled on maximum doses of metformin or sulfonylurea (glyburide, gliclazide, or glimepiride) to compare the time to reach the combined cardiovascular endpoint of cardiovascular death or cardiovascular hospitalization between patients randomized to the addition of rosiglitazone versus metformin or sulfonylurea. The trial included patients who have failed metformin or sulfonylurea monotherapy; those who failed metformin (n = 2,222) were randomized to receive either add-on rosiglitazone (n = 1,117) or add-on sulfonylurea (n = 1,105), and those who failed sulfonylurea (n = 2,225) were randomized to receive either add-on rosiglitazone (n = 1,103) or add-on metformin (n = 1,122). Patients were treated to target HbA1c ≤ 7% throughout the trial.

The mean age of patients in this trial was 58 years, 52% were male, and the mean duration of follow-up was 5.5 years. Rosiglitazone demonstrated non-inferiority to active control for the primary endpoint of cardiovascular hospitalization or cardiovascular death (HR 0.99, 95% CI: 0.85-1.16). There were no significant differences between groups for secondary endpoints with the exception of congestive heart failure (see Table 5). The incidence of congestive heart failure was significantly greater among patients randomized to rosiglitazone.

Table 5: Cardiovascular (CV) Outcomes for the RECORD Trial

There was an increased incidence of bone fracture for subjects randomized to rosiglitazone in addition to metformin or sulfonylurea compared with those randomized to metformin plus sulfonylurea (8.3% versus 5.3%) [see WARNINGS AND PRECAUTIONS]. The majority of fractures were reported in the upper limbs and distal lower limbs. The risk of fracture appeared to be higher in females relative to control (11.5% versus 6.3%), than in males relative to control (5.3% versus 4.3%). Additional data are necessary to determine whether there is an increased risk of fracture in males after a longer period of follow-up.

Glimepiride: Approximately 2,800 patients with type 2 diabetes have been treated with glimepiride in the controlled clinical trials. In these trials, approximately 1,700 patients were treated with glimepiride for at least 1 year.

Table 6 summarizes adverse events, other than hypoglycemia, that were reported in 11 pooled placebo-controlled trials, whether or not considered to be possibly or probably related to study medication. Treatment duration ranged from 13 weeks to 12 months. Terms that are reported represent those that occurred at an incidence of ≥ 5% among glimepiride-treated patients and more commonly than in patients who received placebo.

Table 6: Eleven Pooled Placebo-Controlled Trials Ranging From 13 Weeks to 12 Months: Adverse Events (Excluding Hypoglycemia) Occurring in ≥ 5% of Glimepiride-Treated Patients and at a Greater Incidence Than With Placeboa

Hypoglycemia: In a randomized, double-blind, placebo-controlled monotherapy trial of 14 weeks duration, patients already on sulfonylurea therapy underwent a 3-week washout period then were randomized to glimepiride 1 mg, 4 mg, 8 mg or placebo. Patients randomized to glimepiride 4 mg or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated. The overall incidence of possible hypoglycemia (defined by the presence of at least one symptom that the investigator believed might be related to hypoglycemia; a concurrent glucose measurement was not required) was 4% for glimepiride 1 mg, 17% for glimepiride 4 mg, 16% for glimepiride 8 mg, and 0% for placebo. All of these events were self-treated.

In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration, patients received a starting dose of either 1 mg glimepiride or placebo daily. The dose of glimepiride was titrated to a target fasting plasma glucose of 90 to 150 mg/dL. Final daily doses of glimepiride were 1, 2, 3, 4, 6, or 8 mg. The overall incidence of possible hypoglycemia (as defined above for the 14-week trial) for glimepiride versus placebo was 19.7% versus 3.2%. All of these events were self-treated.

Weight Gain: Glimepiride, like all sulfonylureas, can cause weight gain.

Allergic Reactions: In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in less than 1% of glimepiride-treated patients. These may resolve despite continued treatment with glimepiride. There are postmarketing reports of more serious allergic reactions (e.g., dyspnea, hypotension, shock) [see WARNINGS AND PRECAUTIONS].

Laboratory Abnormalities

Hematologic: Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone (mean decreases in individual trials as much as 1.0 g/dL hemoglobin and as much as 3.3% hematocrit). The changes occurred primarily during the first 3 months following initiation of therapy with rosiglitazone or following a dose increase in rosiglitazone. The time course and magnitude of decreases were similar in patients treated with a combination of rosiglitazone and other hypoglycemic agents or monotherapy with rosiglitazone. White blood cell counts also decreased slightly in adult patients treated with rosiglitazone. Decreases in hematologic parameters may be related to increased plasma volume observed with treatment with rosiglitazone.

Lipids: Changes in serum lipids have been observed following treatment with rosiglitazone in adults [see CLINICAL PHARMACOLOGY].

Serum Transaminase Levels: In pre-approval clinical trials in 4,598 patients treated with rosiglitazone encompassing approximately 3,600 patient-years of exposure, there was no evidence of drug-induced hepatotoxicity.

In pre-approval controlled trials, 0.2% of patients treated with rosiglitazone had reversible elevations in ALT > 3X the upper limit of normal compared with 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with rosiglitazone were reversible. 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. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure. [See WARNINGS AND PRECAUTIONS]

In the 4- to 6-year ADOPT trial, patients treated with rosiglitazone (4,954 patient-years exposure), glyburide (4,244 patient-years exposure), or metformin (4,906 patient-years exposure) as monotherapy had the same rate of ALT increase to > 3X upper limit of normal (0.3 per 100 patient-years exposure).

In the RECORD trial, patients randomized to rosiglitazone in addition to metformin or sulfonylurea (10,849 patient-years exposure) and to metformin plus sulfonylurea (10,209 patient-years exposure) had a rate of ALT increase to ≥ 3X upper limit of normal of approximately 0.2 and 0.3 per 100 patient-years exposure, respectively.

Glimepiride: Serum Transaminase Levels: In 11 pooled, placebo-controlled trials of glimepiride, 1.9% of glimepiride-treated patients and 0.8% of placebo-treated patients developed serum ALT > 2X the upper limit of the reference range.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of AVANDARYL or its individual components. Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure.

Rosiglitazone: In patients receiving thiazolidinedione therapy, serious adverse events with or without a fatal outcome, potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported [see BOXED WARNING, WARNINGS AND PRECAUTIONS].

There are postmarketing reports with rosiglitazone of hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of normal, and hepatic failure with and without fatal outcome, although causality has not been established.

There are postmarketing reports with rosiglitazone of rash, pruritus, urticaria, angioedema, anaphylactic reaction, Stevens-Johnson syndrome [see CONTRAINDICATIONS], and new onset or worsening diabetic macular edema with decreased visual acuity [see WARNINGS AND PRECAUTIONS].

• Serious hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome [see WARNINGS AND PRECAUTIONS]
• Hemolytic anemia in patients with and without G6PD deficiency [see WARNINGS AND PRECAUTIONS]
• Impairment of liver function (e.g., with cholestasis and jaundice), as well as hepatitis, which may progress to liver failure
• Porphyria cutanea tarda, photosensitivity reactions, and allergic vasculitis
• Leukopenia, agranulocytosis, aplastic anemia, and pancytopenia
• Thrombocytopenia (including severe cases with platelet count less than 10,000/μL) and thrombocytopenic purpura
• Hepatic porphyria reactions and disulfiram-like reactions
• Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH), most often in patients who are on other medications or who have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone

Included as part of the PRECAUTIONS section.

Glimepiride and rosiglitazone is a combination of two oral diabetes medicines that help control blood sugar levels.

Glimepiride and rosiglitazone is for people with type 2 diabetes. This medication is not for treating type 1 diabetes. Glimepiride and rosiglitazone is not recommended for use with insulin.

Taking glimepiride and rosiglitazone may increase your risk of serious heart problems, such as heart attack or stroke. Therefore, glimepiride and rosiglitazone is available only to certain people with type 2 diabetes that cannot be controlled with other diabetes medications.

Glimepiride and rosiglitazone is available only under a special program called Avandia-Rosiglitazone Medicines Access Program. You must be registered in the program and sign documents stating that you understand the risks and benefits of taking this medication.

Glimepiride and rosiglitazone may also be used for purposes not listed in this medication guide.

You should not use glimepiride and rosiglitazone if you have advanced heart failure if you are in a state of diabetic ketoacidosis (call your doctor for treatment).

To make sure you can safely take glimepiride and rosiglitazone, tell your doctor if you have any of these other conditions:

• congestive heart failure, heart disease, a history of heart attack or stroke;
• an enzyme deficiency called glucose-6-phosphate dehydrogenase deficiency (G6PD);
• liver disease or kidney disease;
• adrenal or pituitary gland disorders; or
• eye problems caused by diabetes.

Certain oral diabetes medications may increase your risk of serious heart problems. However, not treating your diabetes can damage your heart and other organs. Talk to your doctor about the risks and benefits of treating your diabetes with glimepiride and rosiglitazone.

Women may be more likely than men to have bone fractures in the upper arm, hand, or foot while taking glimepiride and rosiglitazone. Talk with your doctor if you are concerned about this possibility.

FDA pregnancy category C. Do not use glimepiride and rosiglitazone if you are pregnant. It is not known whether this medication will harm an unborn baby. Similar diabetes medications have caused severe hypoglycemia in newborn babies whose mothers had used the medication near the time of delivery. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Some women using glimepiride and rosiglitazone have started having menstrual periods, even after not having a period for a long time due to a medical condition. You may be able to get pregnant if your periods restart. Talk with your doctor about the need for birth control.

It is not known whether glimepiride and rosiglitazone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using glimepiride and rosiglitazone.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Avoid drinking alcohol. It can lower your blood sugar.

Avoid exposure to sunlight or tanning beds. This medication can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.