İHALE DÜNYASI
İHALE DÜNYASI
ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels. Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the ?-glucosidase inhibitors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo . No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown: Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of C 19 H 20 N 2 O 3 S*HCl and a molecular weight of 392.90 daltons. It is soluble in N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF. Chemical Structure
ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
ACTOS should be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA 1c which is a better indicator of long-term glycemic control than FPG alone. HbA 1c reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with ACTOS for a period of time adequate to evaluate change in HbA 1c (three months) unless glycemic control deteriorates. After initiation of ACTOS or with dose increase, patients should be carefully monitored for adverse events related to fluid retention (see BOXED WARNING and WARNINGS ). Monotherapy ACTOS monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of ACTOS, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Combination Therapy Sulfonylureas : ACTOS in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased. Metformin : ACTOS in combination with metformin may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypoglycemia during combination therapy with ACTOS. Insulin : ACTOS in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of ACTOS therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Maximum Recommended Dose The dose of ACTOS should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin. Dose adjustment in patients with renal insufficiency is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism ). Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General , Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations , Hepatic Insufficiency ). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOS and periodically thereafter (see PRECAUTIONS, General , Hepatic Effects ). There are no data on the use of ACTOS in patients under 18 years of age; therefore, use of ACTOS in pediatric patients is not recommended. No data are available on the use of ACTOS in combination with another thiazolidinedione.
Initiation of ACTOS in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated (see BOXED WARNING ). ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components.
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 7 . Table 7 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency ? 5% of Patients Treated with ACTOS (% of Patients) Placebo N=259 ACTOS 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 For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General , Hypoglycemia and DOSAGE and ADMINISTRATION, Combination Therapy ). In U.S. double-blind studies, anemia was reported in ? 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General , Hematologic ). In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 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 HbA 1c 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 8 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 8 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 , 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, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS 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 , Hepatic Effects ). CPK Levels : During required laboratory testing in clinical trials, 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 ACTOS, 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 ACTOS therapy is unknown.
Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of ACTOS must be considered (see BOXED WARNING ). Patients with NYHA Class III and IV cardiac status were not studied during pre-approval clinical trials and ACTOS is not recommended in these patients (see BOXED WARNING and CONTRAINDICATIONS ). In one 16-week, U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study, two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week, dose-controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0.9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetes and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA 1c 8.8% at baseline) with NYHA Class II and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. 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 once daily, or placebo (n=2633) (see ADVERSE REACTIONS ). The percentage of patients who had an event of serious heart failure was higher for patients treated with ACTOS (5.7%, n=149) than for patients treated with placebo (4.1%, n=108). The incidence of death subsequent to a report of serious heart failure was 1.5% (n=40) in patients treated with ACTOS and 1.4% (n=37) in placebo-treated patients. In patients treated with an insulin-containing regimen at baseline, the incidence of serious heart failure was 6.3% (n=54/864) with ACTOS and 5.2% (n=47/896) with placebo. For those patients treated with a sulfonylurea-containing regimen at baseline, the incidence of serious heart failure was 5.8% (n=94/1624) with ACTOS and 4.4% (n=71/1626) with placebo. --- BOXED WARNING: WARNING: CONGESTIVE HEART FAILURE Thiazolidinediones, including ACTOS, cause or exacerbate congestive heart failure in some patients (see WARNINGS ). After initiation of ACTOS, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to the current standards of care. Furthermore, discontinuation or dose reduction of ACTOS must be considered. ACTOS is not recommended in patients with symptomatic heart failure. Initiation of ACTOS in patients with established NYHA Class III or IV heart failure is contraindicated (see CONTRAINDICATIONS and WARNINGS ). | Figure 1 Mean Change from Baseline for FPG and HbA 1c in a 26-Week Placebo- Controlled Dose-Ranging Study
Drug-Drug Interactions The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results: Oral Contraceptives : Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and C max respectively. There were no significant changes in norethindrone AUC (0-24h) and C max . In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown. Fexofenadine HCl : Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally twice daily resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics. Glipizide : Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Digoxin : Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin. Warfarin : Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy. Metformin : Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin. Midazolam : Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam C max and AUC. Ranitidine HCl : Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics. Nifedipine ER : Co-administration of ACTOS for 7 days with 30 mg nifedipine ER administered orally once daily for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for C max and 0.88 (0.80 - 0.96) for AUC. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown. Ketoconazole : Co-administration of ACTOS for 7 days with ketoconazole 200 mg administered twice daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for C max , 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for C min . Atorvastatin Calcium : Co-administration of ACTOS for 7 days with atorvastatin calcium (LIPITOR(R)) 80 mg once daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 0.69 (0.57 - 0.85) for C max , 0.76 (0.65 - 0.88) for AUC and 0.96 (0.87 - 1.05) for C min . For unchanged atorvastatin the least square mean (90% CI) values were 0.77 (0.66 - 0.90) for C max , 0.86 (0.78 - 0.94) for AUC and 0.92 (0.82 - 1.02) for C min . Theophylline : Co-administration of ACTOS for 7 days with theophylline 400 mg administered twice daily resulted in no change in the pharmacokinetics of either drug. Cytochrome P450 : See PRECAUTIONS Gemfibrozil : Concomitant administration of gemfibrozil (oral 600 mg twice daily), an inhibitor of CYP2C8, with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 2 days prior with gemfibrozil (oral 600 mg twice daily) resulted in pioglitazone exposure (AUC 0-24 ) being 226% of the pioglitazone exposure in the absence of gemfibrozil (see PRECAUTIONS ). 1 Rifampin : Concomitant administration of rifampin (oral 600 mg once daily), an inducer of CYP2C8 with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 5 days prior with rifampin (oral 600 mg once daily) resulted in a decrease in the AUC of pioglitazone by 54% (see PRECAUTIONS ). 2 | Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions ). 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 (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions ).