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adverse reactions
6 ADVERSE REACTIONS The most common adverse reactions (≥10%) include nausea/vomiting, diarrhea, headache, and dyspepsia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Med-Health Pharma, LLC at 1-877-896-6654 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The incidence and types of adverse events reported in controlled, 26-week clinical trials of rosiglitazone administered in combination with metformin 2,500 mg/day in comparison to adverse reactions reported in association with rosiglitazone and metformin monotherapies are shown in Table 7. Overall, the types of adverse reactions without regard to causality reported when rosiglitazone was used in combination with metformin were similar to those reported during monotherapy with rosiglitazone. Table 7. Adverse Events (≥5% for Rosiglitazone Plus Metformin) Reported by Patients in 26-week Double-blind Clinical Trials of Rosiglitazone Added to Metformin Therapy Rosiglitazone + Metformin Rosiglitazone Placebo Metformin N = 338 N = 2,526 N = 601 N = 225 Preferred term % % % % Upper respiratory tract infection 16.0 9.9 8.7 8.9 Diarrhea 12.7 2.3 3.3 15.6 Injury 8.0 7.6 4.3 7.6 Anemia 7.1 1.9 0.7 2.2 Headache 6.5 5.9 5.0 8.9 Sinusitis 6.2 3.2 4.5 5.3 Fatigue 5.9 3.6 5.0 4.0 Back pain 5.0 4.0 3.8 4.0 Viral infection 5.0 3.2 4.0 3.6 Arthralgia 5.0 3.0 4.0 2.2 Reports of hypoglycemia in patients treated with rosiglitazone added to maximum metformin therapy in double-blind trials 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. 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. 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 trials [see Adverse Reactions (6.2)] . 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 trials of rosiglitazone added to insulin, edema was reported with higher frequency (rosiglitazone in combination with insulin, 14.7%; insulin, 5.4%) [see Warnings and Precautions (5.2)] . In trials in which rosiglitazone was added to insulin, rosiglitazone increased the risk of congestive heart failure. The use of rosiglitazone in combination with insulin may increase the risk of myocardial infarction [see Warnings and Precautions (5.2, 5.3)] . In a trial in which insulin was added to AVANDAMET, no myocardial ischemia was observed in the insulin group (N = 158), and no congestive heart failure was reported in either group. There was one myocardial ischemic event and one sudden death in the group receiving AVANDAMET plus insulin (N = 161). [See Warnings and Precautions (5.2).] The incidence of anemia was 2% for AVANDAMET in combination with insulin compared to 1% for insulin monotherapy. A long-term, 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 8 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 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 women who received rosiglitazone were reported in the upper arm, hand, and foot. [See Warnings and Precautions (5.8).] The observed incidence of fractures for male patients was similar among the 3 treatment groups. Table 8. 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) Rosiglitazone Glyburide Metformin N = 1,456 N = 1,441 N = 1,454 PY = 4,954 PY = 4,244 PY = 4,906 Nasopharyngitis 6.3 6.9 6.6 Back pain 5.1 4.9 5.3 Arthralgia 5.0 4.8 4.2 Hypertension 4.4 6.0 6.1 Upper respiratory tract infection 4.3 5.0 4.7 Hypoglycemia 2.9 13.0 3.4 Diarrhea 2.5 3.2 6.8 6.2 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 gram/dL hemoglobin and as much as 3.3% hematocrit). The changes occurred primarily during the first 3 months following initiation of rosiglitazone therapy or following an increase in rosiglitazone dose. 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. Pre-treatment levels of hemoglobin and hematocrit were lower in patients in metformin combination trials and may have contributed to the higher reporting rate of anemia. In a single trial 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 of 29 weeks’ duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such a decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Lipids: Changes in serum lipids have been observed following treatment with rosiglitazone in adults [see Clinical Pharmacology (12.2)] . Serum Transaminase Levels: In pre-approval clinical trials in 4,598 patients treated with rosiglitazone encompassing approximately 3,600 patient years of exposure, and in a long-term 4- to 6-year trial in 1,456 patients treated with rosiglitazone (4,954 patient-years 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 to 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 (5.6).] 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). 6.3 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 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 and Precautions (5.2)] . 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, and new onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions (5.7)] . (See also GLUCOPHAGE ® prescribing information.)