Managed Care - March 2008 - (Page 2) adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate. An enzyme inhibitor of CYP2C8 (such as gemfibrozil) may significantly increase the AUC of pioglitazone and an enzyme inducer of CYP2C8 (such as rifampin) may significantly decrease the AUC of pioglitazone. Therefore, if an inhibitor or inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response. Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m2). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m2). No drug-induced tumors were observed in any organ. During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors were identified. In two 3-year studies in which pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) on placebo. Pioglitazone HCl was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCl daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m2). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCl (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m2). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m2). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m2, respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m2). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m2). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m2). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman. Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS Over 8500 patients with type 2 diabetes have been treated with ACTOS in randomized, double-blind, controlled clinical trials. This includes 2605 high-risk patients with type 2 diabetes treated with ACTOS 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 ACTOS for at least 2 years. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 2. Table 2 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency ≥ 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1 7.2% of patients treated with ACTOS and sulfonylureas compared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6.0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7.0% of patients on insulin alone. Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects). 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 HbA1c 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 3 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 3 Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint Placebo N=2633 First Events Total Events (N) (N) 572 900 122 186 118 157 96 119 63 78 101 240 15 28 57 92 ACTOS N=2605 First Events Total Events (N) (N) 514 803 110 177 105 131 76 92 42 65 101 195 9 28 71 115 Cardiovascular Events Any event All-cause mortality Non-fatal MI Stroke ACS Cardiac intervention Major leg amputation Leg revascularization Postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see PRECAUTIONS, General, Macular Edema). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. 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 ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS 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 ACTOS, mean values for bilirubin, AST, ALT,
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