ADVERSE REACTIONS
The adverse events reported in at least 5% of patients in the controlled 16-week clinical studies between placebo plus a sulfonylurea and pioglitazone (15 mg and 30 mg combined) plus sulfonylurea-treatment arms were upper respiratory tract infection (15.5% and 16.6%), accidental injury (8.6% and 3.5%) and combined edema/peripheral edema (2.1% and 7.2%), respectively.
The incidence and type of adverse events reported in at least 5% of patients in any combined treatment group from the 24-week study comparing pioglitazone 30 mg plus a sulfonylurea and pioglitazone 45 mg plus a sulfonylurea are shown in Table 4; the rate of adverse events resulting in study discontinuation between the two treatment groups was 6.0% and 9.7%, respectively.
Table 4. Adverse Events That Occurred in ≥ 5% of Patients in Any Treatment Group During the 24-Week Study Adverse Event
| Pioglitazone 30 mg+ sulfonylurea
N=351
n (%) | Pioglitazone 45 mg+ sulfonylurea
N=351
n (%) |
| Hypoglycemia | 47 (13.4) | 55 (15.7) |
| Upper Respiratory Tract Infection | 43 (12.3) | 52 (14.8) |
| Weight Increased | 32 (9.1) | 47 (13.4) |
| Edema Lower Limb | 20 (5.7) | 43 (12.3) |
| Headache | 25 (7.1) | 14 (4.0) |
| Urinary Tract Infection | 20 (5.7) | 24 (6.8) |
| Diarrhea | 21 (6.0) | 15 (4.3) |
| Nausea | 18 (5.1) | 14 (4.0) |
| Pain in Limb | 19 (5.4) | 14 (4.0) |
In U.S. double-blind studies, anemia was reported in ≤ 2% of patients treated with pioglitazone plus a sulfonylurea (see PRECAUTIONS, General: Pioglitazone hydrochloride ).
Pioglitazone hydrochloride
Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials. This includes 2605 high-risk patients with type 2 diabetes treated with pioglitazone from the PROactive clinical trial. Over 6000 patients have been treated for 6 months or longer, and over 4500 patients for one year or longer. Over 3000 patients have received pioglitazone for at least 2 years.
Most clinical adverse events were similar between groups treated with pioglitazone in combination with a sulfonylurea and those treated with pioglitazone monotherapy. Other adverse events reported in at least 5% of patients in controlled clinical studies between placebo and pioglitazone monotherapy included myalgia (2.7% and 5.4%), tooth disorder (2.3% and 5.3%), diabetes mellitus aggravated (8.1% and 5.1%) and pharyngitis (0.8% and 5.1%), respectively.
In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with pioglitazone versus 1.2% of placebo-treated patients. Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General: Pioglitazone hydrochloride, Edema ).
Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive)
In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg daily, or placebo (n=2633), in addition to standard of care. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, ARBs, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates). Patients had a mean age of 61.8 years, mean duration of diabetes 9.5 years, and mean A1C 8.1%. Average duration of follow-up was 34.5 months. The primary objective of this trial was to examine the effect of ACTOS on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in the cardiovascular composite endpoint (see table 5 below). Although there was no statistically significant difference between ACTOS and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with ACTOS.
Table 5. Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint |
|
| Placebo
N=2633 | ACTOS
N=2605 |
| Cardiovascular Events | First Events
(N) | Total events
(N) | First Events
(N) | Total events
(N) |
| Any event | 572 | 900 | 514 | 803 |
| All-cause mortality | 122 | 186 | 110 | 177 |
| Non-fatal MI | 118 | 157 | 105 | 131 |
| Stroke | 96 | 119 | 76 | 92 |
| ACS | 63 | 78 | 42 | 65 |
| Cardiac intervention | 101 | 240 | 101 | 195 |
| Major leg amputation | 15 | 28 | 9 | 28 |
| Leg revascularization | 57 | 92 | 71 | 115 |
Postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see PRECAUTIONS, General: Pioglitazone hydrochloride ).
Glimepiride
Adverse events that occurred in controlled clinical trials with placebo and glimepiride monotherapy, other than hypoglycemia, headache and nausea, also included dizziness (0.3% and 1.7%) and asthenia (1.0% and 1.6%), respectively.
Gastrointestinal Reactions: Vomiting, gastrointestinal pain, and diarrhea have been reported with glimepiride, but the incidence in placebo-controlled trials was less than 1%. In rare cases, there may be an elevation of liver enzyme levels. In isolated instances, impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may also lead to liver failure have been reported with sulfonylureas, including glimepiride.
Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in less than 1% of glimepiride-treated patients. These may be transient and may disappear despite continued use of glimepiride. If those hypersensitivity reactions persist or worsen, the drug should be discontinued. Porphyria cutanea tarda, photosensitivity reactions, and allergic vasculitis have been reported with sulfonylureas.
Metabolic Reactions: Hepatic porphyria reactions and disulfiram-like reactions have been reported with sulfonylureas; however, no cases have yet been reported with glimepiride tablets. Cases of hyponatremia have been reported with glimepiride and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.
Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.
Other Reactions: Changes in accommodation and/or blurred vision may occur with the use of glimepiride. In placebo-controlled trials of glimepiride, the incidence of blurred vision with placebo was 0.7%, and with glimepiride, 0.4%. This is thought to be due to changes in blood glucose, and may be more pronounced when treatment is initiated. This condition is also seen in untreated diabetic patients, and may actually be reduced by treatment.
Laboratory Abnormalities
Pioglitazone hydrochloride
Hematologic: Pioglitazone may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with pioglitazone appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone. These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and have rarely been associated with any significant hematologic clinical effects (see PRECAUTIONS, General: Pioglitazone hydrochloride, Hematologic ).
Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with pioglitazone had ALT values ≥ 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with pioglitazone, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with pioglitazone were withdrawn from clinical trials in the U.S. due to abnormal liver function tests.
In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, General: Pioglitazone hydrochloride, Hepatic Effects ).
CPK Levels: During required laboratory testing in clinical trials with pioglitazone, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive pioglitazone, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown.
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