The incidence and types of adverse events reported in a controlled, 32-week double-blind clinical trial of AVANDAMET in drug-naïve patients (n = 468) are shown in Table 8.

Table 8. Adverse Events (> 5% in Any Treatment Group) Reported by Drug-Naïve Patients in a 32-week Double-blind Clinical Trial of AVANDAMET

The incidence and types of adverse events reported in controlled, 26-week clinical trials of rosiglitazone maleate administered in combination with metformin hydrochloride 2,500 mg/day in comparison to adverse reactions reported in association with rosiglitazone and metformin monotherapies are shown in Table 9. Overall, the types of adverse experiences reported when rosiglitazone was used in combination with metformin were similar to those reported during monotherapy with rosiglitazone.

Table 9. Adverse Events (≥ 5% in Any Treatment Group) Reported by Patients in 26-week Double-blind Clinical Trials of Rosiglitazone Added to Metformin Therapy

In the double-blind trial evaluating AVANDAMET in drug-naïve patients, mild (no intervention required) to moderate (minor intervention required) symptomatic hypoglycemia was reported by 18/155 (12%) of patients treated with AVANDAMET, 14/154 (9%) with metformin, and 13/159 (8%) with rosiglitazone. Approximately half of these episodes were accompanied by a simultaneous capillary glucose measurement, and the rate of confirmed hypoglycemia (blood glucose ≤ 50mg/dL) was low in this clinical study: 0.6% (1/155) for AVANDAMET, 1.3% (2/154) for metformin and 0% with rosiglitazone. No hypoglycemic episode led to withdrawal with AVANDAMET treatment, and no patients required medical intervention due to hypoglycemia.

Reports of hypoglycemia in patients treated with rosiglitazone added to maximum metformin therapy in double-blind studies were more frequent (3.0%) than in patients treated with rosiglitazone (0.6%) or metformin monotherapies (1.3%) or placebo (0.2%). Overall, anemia and edema were generally mild to moderate in severity and usually did not require discontinuation of treatment with rosiglitazone.

In the double-blind trial in drug-naïve patients, the incidence of edema was 6% on AVANDAMET compared to 7% on rosiglitazone and 3% on metformin.

In the double-blind trial in drug-naïve patients, the incidence of anemia was 4% in patients treated with AVANDAMET compared to either rosiglitazone (2%) or metformin (0%). Reports of anemia (7.1%) were greater in patients treated with rosiglitazone added to metformin compared to monotherapy with rosiglitazone. Lower pre-treatment hemoglobin/hematocrit levels in patients enrolled in the metformin and rosiglitazone combination therapy clinical trials may have contributed to the higher reporting rate of anemia in these studies (see ADVERSE REACTIONS, Laboratory Abnormalities, Hematologic).

Edema was reported in 4.8% of patients receiving 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.

Combination with Insulin

The safety profile for AVANDAMET plus insulin was consistent with that of the individual components (rosiglitazone or metformin) and with that of rosiglitazone used in combination with insulin.

The incidence of hypoglycemia (confirmed by fingerstick blood glucose concentration ≤ 50 mg/dL) was 14% for patients on AVANDAMET plus insulin compared to 10% for patients on insulin monotherapy.

The incidence of edema was 7% when insulin was added to AVANDAMET compared to 3% with insulin monotherapy. This trial excluded patients with pre-existing heart failure or new or worsening edema on AVANDAMET therapy.

However, in 26-week double-blind, fixed-dose studies of rosiglitazone added to insulin, edema was reported with higher frequency (rosiglitazone in combination with insulin, 14.7%; insulin, 5.4%). 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. There were too few events to confirm a dose relationship; however, the incidence of heart failure appeared higher with rosiglitazone 8 mg daily (see BOXED WARNING and WARNINGS, Rosiglitazone maleate).

The incidence of anemia was 2% for AVANDAMET in combination with insulin compared to 1% for insulin monotherapy.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of AVANDAMET 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.

In postmarketing experience 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 and WARNINGS, Rosiglitazone maleate).

Rash, pruritus, urticaria, angioedema, anaphylactic reaction, and Stevens-Johnson syndrome have been reported rarely.

Reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see PRECAUTIONS, Rosiglitazone maleate, Macular Edema).

(See also GLUCOPHAGE prescribing information, ADVERSE REACTIONS.)

Laboratory Abnormalities

Hematologic

Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone maleate (mean decreases in individual studies up to 1.0 gram/dL hemoglobin and up to 3.3% hematocrit). The time course and magnitude of decreases were similar in patients treated with a combination of rosiglitazone and other hypoglycemic agents or rosiglitazone monotherapy. Pre-treatment levels of hemoglobin and hematocrit were lower in patients in metformin combination studies and may have contributed to the higher reporting rate of anemia. In a single study in pediatric patients, decreases in hemoglobin and hematocrit (mean decreases of 0.29 g/dL and 0.95%, respectively) were reported 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 rosiglitazone treatment.

In controlled clinical trials of metformin hydrochloride of 29 weeks' duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂ levels, without clinical manifestations, was observed in approximately 7% of patients. 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.

Lipids

Changes in serum lipids have been observed following treatment with rosiglitazone maleate in adults (see CLINICAL STUDIES). Small changes in serum lipid parameters were reported in children treated with rosiglitazone for 24 weeks.

Serum Transaminase Levels

In clinical studies in 4,598 patients treated with rosiglitazone maleate encompassing approximately 3,600 patient years of exposure, there was no evidence of drug-induced hepatotoxicity or elevated ALT levels.

In controlled trials, 0.2% of patients treated with rosiglitazone maleate had reversible elevations in ALT > 3X the upper limit of normal 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.

In the clinical program including long-term, open-label experience, the rate per 100 patient years of exposure of ALT increase to > 3X the upper limit of normal was 0.35 for patients treated with rosiglitazone maleate, 0.59 for placebo-treated patients, and 0.78 for patients treated with active comparator agents.

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure. In postmarketing experience with rosiglitazone maleate, reports of hepatic enzyme elevations 3 or more times the upper limit of normal and hepatitis have been received (see PRECAUTIONS, Hepatic Effects).

An inhibitor of CYP2C8 (such as gemfibrozil) may increase the AUC of rosiglitazone and an inducer of CYP2C8 (such as rifampin) may decrease the AUC of rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response.

Although drug interactions with cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of AVANDAMET and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

When drugs that produce hyperglycemia which may lead to loss of glycemic control are administered to a patient receiving AVANDAMET, the patient should be closely observed to maintain adequate glycemic control. (See CLINICAL PHARMACOLOGY: Drug Interactions.)

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