ADVERSE REACTIONS
Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections.
PRANDIN has been administered to 2931 individuals during clinical trials. Approximately 1500 of these individuals with type 2 diabetes have been treated for at least 3 months, 1000 for at least 6 months, and 800 for at least 1 year. The majority of these individuals (1228) received PRANDIN in one of five 1-year, active-controlled trials. The comparator drugs in these 1-year trials were oral sulfonylurea drugs (SU) including glyburide and glipizide. Over one year, 13% of PRANDIN patients were discontinued due to adverse events, as were 14% of SU patients. The most common adverse events leading to withdrawal were hyperglycemia, hypoglycemia, and related symptoms (see PRECAUTIONS). Mild or moderate hypoglycemia occurred in 16% of PRANDIN patients, 20% of glyburide patients, and 19% of glipizide patients.
The table below lists common adverse events for PRANDIN patients compared to both placebo (in trials 12 to 24 weeks duration) and to glyburide and glipizide in one year trials. The adverse event profile of PRANDIN was generally comparable to that for sulfonylurea drugs (SU).
Commonly Reported Adverse Events (% of Patients) *
|
EVENT
|
PRANDIN
N = 352
|
PLACEBO
N = 108
|
PRANDIN
N = 1228
|
SU
N = 498
|
|
|
Placebo controlled
studies
|
Active controlled
studies
|
| Metabolic |
|
Hypoglycemia
|
31 ** |
7
|
16
|
20
|
| Respiratory |
|
URI
|
16
|
8
|
10
|
10
|
|
Sinusitis
|
6
|
2
|
3
|
4
|
|
Rhinitis
|
3
|
3
|
7
|
8
|
|
Bronchitis
|
2
|
1
|
6
|
7
|
| Gastrointestinal |
|
Nausea
|
5
|
5
|
3
|
2
|
|
Diarrhea
|
5
|
2
|
4
|
6
|
|
Constipation
|
3
|
2
|
2
|
3
|
|
Vomiting
|
3
|
3
|
2
|
1
|
|
Dyspepsia
|
2
|
2
|
4
|
2
|
| Musculoskeletal |
|
Arthralgia
|
6
|
3
|
3
|
4
|
|
Back Pain
|
5
|
4
|
6
|
7
|
| Other |
|
Headache
|
11
|
10
|
9
|
8
|
|
Paresthesia
|
3
|
3
|
2
|
1
|
|
Chest pain
|
3
|
1
|
2
|
1
|
Urinary tract
infection
|
2
|
1
|
3
|
3
|
|
Tooth disorder
|
2
|
0
|
<1 |
<1 |
|
Allergy
|
2
|
0
|
1
|
<1 |
|
*: Events >/= 2% for the PRANDIN group in the placebo-controlled studies and >/= events in the placebo group
|
|
**: See trial description in CLINICAL PHARMACOLOGY, Clinical Trials |
|
Cardiovascular events also occur commonly in patients with type 2 diabetes. In one-year comparator trials, the incidence of individual events was not greater than 1% except for chest pain (1.8%) and angina (1.8%). The individual incidence of other cardiovascular events (hypertension, abnormal EKG, myocardial infarction, arrhythmias, and palpitations) was
The incidence of serious cardiovascular adverse events added together, including ischemia, was slightly higher for repaglinide (4%) than for sulfonylurea drugs (3%) in controlled comparator clinical trials. In 1-year controlled trials, PRANDIN treatment was not associated with excess mortality rates compared to rates observed with other oral hypoglycemic agent therapies.
Summary of Serious Cardiovascular Events (% of total patients with events)
|
|
PRANDIN
|
SU * |
|
Total Exposed
|
1228
|
498
|
|
Serious CV Events
|
4%
|
3%
|
Cardiac Ischemic
Events
|
2%
|
2%
|
Deaths due to
CV Events
|
0.5%
|
0.4%
|
|
* glyburide and glipizide
|
|
INFREQUENT ADVERSE EVENTS (<1% OF PATIENTS)
Less common adverse clinical or laboratory events observed in clinical trials included elevated liver enzymes, thrombocytopenia, leukopenia, and anaphylactoid reactions (one patient).
COMBINATION THERAPY WITH THIAZOLIDINEDIONES
During 24-week treatment clinical trials of PRANDIN-rosiglitazone or PRANDIN-pioglitazone combination therapy (a total of 250 patients in combination therapy), hypoglycemia (blood glucose < 50 mg/dL) occurred in 7% of combination therapy patients in comparison to 7% for PRANDIN monotherapy, and 2% for thiazolidinedione monotherapy.
Peripheral edema was reported in 12 out of 250 PRANDIN-thiazolidinedione combination therapy patients and 3 out of 124 thiazolidinedione monotherapy patients, with no cases reported in these trials for PRANDIN monotherapy. When corrected for dropout rates of the treatment groups, the percentage of patients having events of peripheral edema per 24 weeks of treatment were 5% for PRANDIN-thiazolidinedione combination therapy, and 4% for thiazolidinedione monotherapy. There were reports in 2 of 250 patients (0.8%) treated with PRANDIN-thiazolidinedione therapy of episodes of edema with congestive heart failure. Both patients had a prior history of coronary artery disease and recovered after treatment with diuretic agents. No comparable cases in the monotherapy treatment groups were reported.
Mean change in weight from baseline was + 4.9 kg for PRANDIN-thiazolidinedione therapy. There were no patients on PRANDIN-thiazolidinedione combination therapy who had elevations of liver transaminases (defined as 3 times the upper limit of normal levels).
Although no causal relationship has been established, postmarketing experience includes reports of the following rare adverse events: alopecia, hemolytic anemia, pancreatitis, Stevens-Johnson Syndrome, and severe hepatic dysfunction.
|
