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| Medication |
Strength |
Quantity |
| Actos (pioglitazone) |
15 mg |
90 |
Actos
Pioglitazone HCl
Actos - Actos Side Effects - Actos Information
Pharmacology: Pioglitazone is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output respectively. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARg). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARg nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. Pioglitazone improves glycemic control while reducing circulating insulin levels.
In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.
Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
Pharmacokinetics: Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady state, 2 of the pharmacologically active metabolites of pioglitazone, metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. At steady state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30 to 50% of the peak total pioglitazone serum concentrations and 20 to 25% of the total area under the serum concentration-time curve (AUC).
Maximum serum concentration (C max), AUC, and trough serum concentrations (C min) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 and 30 mg/day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg/day.
Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.
Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63±0.41 (mean±SD) L/kg of body weight. Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (>98%) to serum albumin.
Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30 to 50% of the total peak serum concentrations and 20 to 25% of the total AUC.
Pioglitazone incubated with expressed human P450 or human liver microsomes results in the formation of M-IV and to a much lesser degree, M-II. The major cytochrome P450 isoforms involved in the hepatic metabolism of pioglitazone are CYP2C8 and CYP3A4 (>50% of metabolism) with contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. Ketoconazole inhibited up to 85% of hepatic pioglitazone metabolism in vitro at a concentration equal molar to pioglitazone. At higher than the therapeutic concentrations, pioglitazone had no effect on the reactions mediated by human liver microsomes expressing cytochrome P450 isoforms including CYP2C8 and CYP3A4. In vivo human studies have not been performed to investigate any induction of CYP3A4 by pioglitazone.
Excretion and Elimination: Following oral administration, approximately 15 to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.
The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/h.
Special Populations: Renal Insufficiency: The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 0.5 to 1.0 mL/s [30 to 60 mL/min]) to severe (creatinine clearance <0.5 mL/s [30 mL/min]) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended.
Hepatic Insufficiency: A single-dose, open-label study was conducted to investigate the effects of impaired hepatic function on pioglitazone. A group of 24 subjects was enrolled; 12 with normal hepatic function and 12 with abnormal hepatic function classified as Childs-Pugh Class B or C. Subjects received a 30 mg pioglitazone tablet 10 minutes after a diet-controlled meal, and changes in the serum pharmacokinetic profile and urinary excretion of pioglitazone and its metabolites were then studied. Compared with controls, subjects with impaired hepatic function have a 45% reduction in pioglitazone and total (pioglitazone plus active metabolites) mean peak concentrations but no change in the mean AUC values. The findings of this study showed that the extent of pioglitazone absorption, as indicated by AUC 0, was similar in both normal subjects and individuals with impaired hepatic function. No adverse events attributable to pioglitazone were reported in either group, and no clinically significant changes in baseline laboratory tests, including liver function tests, were observed.
Although no adverse events attributed to drug were noted in any group, pioglitazone should be used with caution in patients with hepatic disease (see Warnings, Hepatic Disease and Precautions, Hepatic Insufficiency).
Geriatrics: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant.
Children: Pharmacokinetic data in the pediatric population are not available.
Gender: Pioglitazone improved glycemic control in both males and females. In controlled clinical trials the mean C max and AUC values were increased 20 to 60% in females. Hemoglobin A 1C (HbA 1c) decreases from baseline were generally greater for females than for males (average mean absolute difference in HbA 1c 0.005). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.
Pharmacodynamics and Clinical Effects: Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower blood glucose concentrations, lower plasma insulin levels, and lower HbA 1c values. Based on results from an open-label extension study, the glucose lowering effects of pioglitazone appear to persist for at least 1 year. The effect of pioglitazone occurs in the absence of weight loss.
Pioglitazone exerts its antihyperglycemic effect in the presence of insulin. Because pioglitazone does not stimulate insulin secretion, hypoglycemia would not be expected in patients treated with pioglitazone alone.
Patients with lipid abnormalities were included in clinical trials with pioglitazone. Overall, patients treated with pioglitazone had significant mean decreases in triglycerides and mean increases in HDL cholesterol, with no significant changes in LDL and total cholesterol. In pharmacodynamic studies of both monotherapy and combination therapy, treatment with pioglitazone was associated with decreases in free fatty acids.
In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels decreased in the 15, 30, and 45 mg pioglitazone dose groups compared to a mean increase in the placebo group. Mean HDL levels increased to a greater extent in the pioglitazone-treated patients than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in pioglitazone-treated patients compared to placebo.
In 2 other monotherapy studies (study duration 24 weeks and 16 weeks), the results were generally consistent with the data above. For pioglitazone-treated patients, the placebo-corrected mean changes from baseline decreased by 21 to 23% for triglycerides, and increased by 5 to 13% for HDL cholesterol.
Note that patients who were taking statins were not excluded from clinical trials. Therefore, in a subset of patients, the lipid-lowering effects of pioglitazone were observed in addition to any beneficial effects of other lipid-lowering agents.
Pioglitazone is also associated with weight gain. The graph (Figure 1) plots the change in body weight for patients who had completed 48 weeks of treatment with pioglitazone in an open-label trial.
The maximum and minimum weight changes observed up to Week 48 from time of entry into this open-label trial for the total patient group were 21.77 kg and - 19.86 kg, respectively (median weight change: 4.54 kg).
Two patients were withdrawn from the study due to reported weight increases of 15.6 kg and 20.8 kg respectively. For the first patient, the investigator believed the weight gain was due to edema, and for the second, a dose of 60 mg of pioglitazone was used, and the patient had dietary factors that could have also contributed to the weight gain. Any abnormally large weight gain experienced by some patients may be due to fluid retention (see Warnings).
Clinical Studies: Monotherapy: Three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of pioglitazone as monotherapy in patients with type 2 diabetes. These studies examined pioglitazone at doses up to 45 mg or placebo once daily in 865 patients. All 3 studies included patients previously treated with another oral antidiabetic agent (sulfonylureas, n=524; metformin, n=170; acarbose, n=19) and patients who were previously untreated (n=268).
In a 26-week dose-ranging study, 408 patients with type 2 diabetes were randomized to receive 7.5, 15, 30, or 45 mg of pioglitazone, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15, 30, and 45 mg of pioglitazone produced statistically significant improvements in HbA 1c and fasting blood glucose (FBG) at endpoint compared to placebo (see Figure 2 and Table II).
For patients who had not been previously treated with antidiabetic medication (24%), mean values at screening were 0.101 for HbA 1c and 13.2 mmol/L for FBG. At baseline, mean HbA 1c was 0.102 and mean FBG was 13.5 mmol/L. Compared with placebo, treatment with pioglitazone titrated to a final dose of 30 and 45 mg resulted in reductions from baseline in mean HbA 1c of 0.023 and 0.026 and mean FBG of 3.5 mmol/L and 5.3 mmol/L, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 0.094 for HbA 1c and 12.0 mmol/L for FBG. At baseline, mean HbA 1c was 0.107 and mean FBG was 16.1 mmol/L. Compared with placebo, treatment with pioglitazone titrated to a final dose of 30 and 45 mg resulted in reductions from baseline in mean HbA 1c of 0.013 and 0.014 and mean FBG of 3.1 mmol/L and 3.3 mmol/L, respectively. The decrease in percent mean HbA 1c was not greater with 45 mg compared to 30 mg.
For patients who had been previously treated with antidiabetic medication, 10% of patients in the final dose of 30 mg, and 4% of patients in the final dose of 45 mg groups did not complete the trial due to an insufficient therapeutic effect. For patients who had not been previously treated with antidiabetic medication, 5% of patients in both groups did not complete the trial due to an insufficient therapeutic effect.
In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of pioglitazone or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of pioglitazone produced statistically significant improvements in HbA 1c and FBG at endpoint compared to placebo (see Table V).
For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 0.103 for HbA 1c and 13.3 mmol/L for FBG. At baseline, mean HbA 1c was 0.104 and mean FBG was 14.1 mmol/L. Compared with placebo, treatment with pioglitazone 30 mg resulted in reductions from baseline in mean HbA 1c of 0.010 and mean FBG of 3.4 mmol/L. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 0.094 for HbA 1c and 12.0 mmol/L for FBG. At baseline, mean HbA 1c was 0.106 and mean FBG was 15.9 mmol/L. Compared with placebo, treatment with pioglitazone 30 mg resulted in reductions from baseline in mean HbA 1c of 0.013 and mean FBG of 2.6 mmol/L. In this study, the response to pioglitazone brought the patients previously treated with other agents back to the values used before entering the trial, i.e., it largely corrected the increase in HbA 1c seen during the run-in period.
A subset analysis was performed on the combined results of the above monotherapy studies to determine if the HbA 1c levels at study entry had an effect on the outcome of the results. There was no meaningful difference in the efficacy of pioglitazone in lowering HbA 1c levels in patients entering the studies with HbA 1c values which were <0.09 compared to those entering with values which were ³0.09.
Combination Therapy: Three 16-week, randomized, double-blind, placebo-controlled clinical studies were conducted to evaluate the effects of pioglitazone on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA 1c ³0.08) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy.
In one combination study, 560 patients with type 2 diabetes on a sulfonylurea, either alone or combined with another antidiabetic agent, were randomized to receive 15 or 30 mg of pioglitazone or placebo once daily in addition to their current sulfonylurea regimen. Any other antidiabetic agent was withdrawn. Compared with placebo, the addition of pioglitazone to the sulfonylurea significantly reduced the mean HbA 1c by 0.009 and 0.013 for the 15 mg and 30 mg doses, respectively. Compared with placebo, mean FBG decreased by 2.2 mmol/L (15 mg dose) and 3.2 mmol/L (30 mg dose). Adverse events most commonly reported were upper respiratory tract infection (16.6%) and edema (5.1%). The therapeutic effect of pioglitazone in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea (<50%, 50%, or >50% of the recommended maximum daily dose). A number of different sufonylureas were used in this study including glyburide (55% of patients) and glipizide (19% of patients).
In a second combination study, 328 patients with type 2 diabetes on metformin either alone or combined with another antidiabetic agent, were randomized to receive either 30 mg of pioglitazone or placebo once daily in addition to their metformin. Any other antidiabetic agent was withdrawn. Compared to placebo, the addition of pioglitazone to metformin significantly reduced the mean HbA 1c by 0.008 and decreased the mean FBG by 2.1 mmol/L. Adverse events most commonly reported were upper respiratory tract infection (15.5%) and headache (6%). The therapeutic effect of pioglitazone in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin (<2000 mg/day or ³2000 mg/day).
In a third combination study, 566 patients with type 2 diabetes receiving a median of 60.5 U/day of insulin, either alone or combined with another antidiabetic agent, were randomized to receive either 15 or 30 mg of pioglitazone or placebo once daily in addition to their insulin. Any other antidiabetic agent was discontinued. Compared to placebo, treatment with pioglitazone in addition to insulin significantly reduced both HbA 1c (reduction of 0.007 for the 15 mg dose and 0.01 for the 30 mg dose) and FBG (1.9 mmol/L for the 15 mg dose and 2.7 mmol/L for the 30 mg dose). Adverse events most commonly reported were hypoglycemia (11.6%), upper respiratory tract infection (11.6%) and edema (11.3%). The therapeutic effect of pioglitazone in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin (<60.5 U/day or ³60.5 U/day).
Indications: As monotherapy in patients not controlled by diet and exercise alone to decrease insulin resistance and blood glucose levels in patients with type 2 diabetes mellitus (non-insulin dependent diabetes mellitus, NIDDM). It is recommended that patients be treated for an adequate period of time to evaluate change in HbA 1c unless glycemic control deteriorates.
Management of type 2 diabetes should also include nutritional counselling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy.
The safety and efficacy of the use of pioglitazone in combination with other antidiabetic agents has not yet been established.
Contraindications: In patients with known hypersensitivity to this product or any of its components. Pioglitazone is contraindicated in patients with serious hepatic impairment (see Precautions, Hepatic Insufficiency).
Warnings: Heart Disease: Treatment with thiazolidinediones has been associated with cases of heart failure which were difficult to treat unless the medication was discontinued. Thiazolidinediones can cause fluid retention, which can exacerbate congestive heart failure. Patients at risk for heart failure, particularly any patient also taking insulin, should be monitored for the signs and symptoms of heart failure. (Clinical evidence for the safety of pioglitazone in combination with other antidiabetic drugs is the subject of ongoing clinical trials.) (see Precautions, Patients with Heart Disease.)
Hepatic Disease: Rare cases of severe hepatocellular injury have been reported associated with thiazolidinediones (see Precautions, Hepatic Insufficiency).
Pregnancy: There are no adequate and well-controlled studies in pregnant women. Pioglitazone should not be used during pregnancy. Current information strongly suggests that abnormally high 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.
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/m 2, 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/m 2). 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/m 2). 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/m 2).
Precautions: General: Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore, pioglitazone should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Hypoglycemia: During the administration of pioglitazone as monotherapy, documented hypoglycemia has not been observed nor would it be expected based on the mechanism of action.
Ovulation: In premenopausal anovulatory patients with insulin resistance, treatment with thiazolidinediones, including pioglitazone, may result in resumption of ovulation. These patients may be at risk for pregnancy if adequate contraception is not used.
Hematologic: Across all clinical studies, mean hemoglobin values declined by 2 to 4% in pioglitazone-treated patients but remained within normal limits at all times (including up to 18 months of continuous therapy). In all studies, patients were excluded if they had a hemoglobin of less than 120 g/L for males or 100 g/L for females. In the monotherapy studies, the mean hemoglobin declined from 151 to 147 g/L, with the range in the bottom 10% of hemoglobin values 111 to 125 g/L. In a long-term open-label follow-up monotherapy study of an additional 84 weeks, the change in hemoglobin remained small, declining from 151 to 143 g/L. In the combination studies, the mean hemoglobin declined from 147 to 142 g/L, with the range in the bottom 10% of hemoglobin values 100 to 124 g/L. In a long-term open-label follow-up combination study of an additional 24 weeks, the change in hemoglobin remained small, declining from 147 to 141 g/L. These changes may be related to increased plasma volume and have not been associated with any significant hematologic clinical effects (see Adverse Effects, Laboratory Abnormalities).
Heart Disease: In a 6-month placebo-controlled study of 334 patients with type 2 diabetes and a long-term (1 year or more) open-label study of more than 350 patients with type 2 diabetes, echocardiographic evaluation revealed no increase in mean left ventricular mass index or decrease in mean cardiac index in patients treated with pioglitazone. Preload-induced cardiac hypertrophy has been observed in some animal toxicology studies.
In clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, ECG evidence of left ventricular hypertrophy, a history of myocardial infarction, coronary angioplasty, coronary bypass graft, unstable angina pectoris, transient ischemic attacks, or a documented cerebrovascular accident 6 months preceding the study, no increased incidence of serious cardiac adverse events potentially related to volume expansion (e.g., congestive heart failure) was observed. Patients with NYHA Class III and IV cardiac status were not studied in pioglitazone clinical trials. There is limited exposure of pioglitazone in patients with Class II cardiac status. Pioglitazone is not indicated in patients with NYHA Class II, III or IV cardiac status unless the expected benefit is believed to outweigh the potential risk. Patients should be monitored for evidence of congestive heart failure.
Edema: Pioglitazone should be used with caution in patients with edema. In studies of 488 nondiabetic subjects, no cases of edema were reported except in 4 patients with concomitant impaired hepatic function and 5 with renal dysfunction. In the monotherapy study, 4.8% of patients on pioglitazone experienced edema, compared with 1.2% on placebo. In a long-term open-label follow-up study of monotherapy, a cumulative incidence of edema of 6% has been reported with pioglitazone. In the combination therapy studies with sulphonylureas, metformin, or insulin, 7.5%, 6%, and 15.3% of patients respectively experienced edema compared with 2.1%, 2.5%, and 7% of patients on placebo, respectively. In a long-term open-label follow-up study of combination therapies, a cumulative incidence of edema of 7.9% has been reported with pioglitazone. Pioglitazone is also associated with weight gain. In the monotherapy studies, improvements in hyperglycemia were associated with mean weight gains ranging 0.5 to 2.8 kg increase in weight. In the combination studies improvements in hyperglycemia were associated with mean weight gains ranging from 0.95 to 3 kg. Patients who experience unusual or unexpected weight gain should be re-evaluated.
Hepatic Disease: Therapy with pioglitazone should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5 times the ULN).
Although available clinical data show no evidence of pioglitazone-induced hepatotoxicity or ALT elevations, pioglitazone has a common thiazolidinedione structure to troglitazone, which has been associated with idiosyncratic hepatotoxicity and rare cases of liver failure, liver transplants, and death. Pending the availability of the results of additional large, long-term controlled clinical trials and postmarket safety data following wide clinical use of pioglitazone to more fully define its hepatic safety profile, it is recommended that patients treated with pioglitazone undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with pioglitazone in all patients. In patients with normal baseline liver enzymes, following initiation of therapy with pioglitazone, it is recommended that liver enzymes be monitored every 2 months for the first 12 months, and periodically thereafter. Patients with mildly elevated liver enzymes (ALT levels 1 to 2.5 times the ULN) at baseline or during therapy with pioglitazone should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of therapy with pioglitazone in patients with mild liver enzyme elevations should proceed with caution and include appropriate close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3 times the ULN in patients on therapy with pioglitazone, liver enzymes should be rechecked as soon as possible. If ALT levels remain >3 times the ULN, therapy with pioglitazone should be discontinued (see Pharmacology, Special Populations, Hepatic Insufficiency).
Children: Safety and effectiveness of pioglitazone in pediatric patients have not been established.
Geriatrics: Approximately 500 patients in placebo-controlled clinical trials of pioglitazone were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients.
Lactation: Pioglitazone is secreted in the milk of lactating rats. It is not known whether pioglitazone is secreted in human milk. Because many drugs are excreted in human milk, pioglitazone should not be administered to a breast-feeding woman.
Information to Be Provided to the Patients: It is important to instruct patients to adhere to dietary instructions, caloric restrictions, weight loss and exercise programs and to have blood glucose and glycosylated hemoglobin tested regularly.
Patients should be told to take pioglitazone once daily. Pioglitazone can be taken with or without meals. If a dose is missed on one day, the patient should take the regular dose on the following day. The patient should not take a double dose to make up for a missed dose.
Although pioglitazone was not associated with hepatic toxicity during clinical trials, patients who develop nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine, jaundice or other symptoms and signs suggestive of hepatic dysfunction should immediately report these to their physician. Patients should be informed that a blood test will be drawn to check their liver function prior to the start of therapy and every 2 months for the first 12 months, and periodically thereafter.
Since thiazolidinediones can cause fluid retention, which can exacerbate congestive heart failure, patients at risk for heart failure should be monitored for the signs and symptoms of heart failure. Patients who develop edema, shortness of breath, weakness, fatigue, or excessive weight gain, should inform their physician immediately and the treatment of these patients should be re-evaluated. If congestive heart failure has developed, stopping treatment with pioglitazone should be considered.
During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly.
Patients should inform their physician if they are taking oral contraceptives. Since pioglitazone may interfere with the metabolism of oral contraceptives, the patient's dose of oral contraceptive may need to be adjusted. Women of childbearing age should inform their physician if they are or intend to become pregnant. In anovulatory, premenopausal women with insulin resistance, therapy with pioglitazone may cause resumption of ovulation and contraceptive measures may need to be considered. Patients who appear to be infertile, should discuss the question of contraceptives before starting therapy with pioglitazone.
Drug Interactions : Oral Contraceptives: Administration of another thiazolidinedione with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both hormones by approximately 30%, which could result in loss of contraception. The pharmacokinetics of coadministration of pioglitazone and oral contraceptives have not been evaluated in patients receiving pioglitazone and an oral contraceptive. Therefore, additional caution regarding contraception should be exercised in patients receiving pioglitazone and an oral contraceptive.
Glipizide: In healthy volunteers, coadministration of pioglitazone (45 mg once daily) and glipizide (5 mg once daily) for 7 days did not alter the steady-state pharmacokinetics of glipizide.
Digoxin: In healthy volunteers, coadministration of pioglitazone (45 mg once daily) with digoxin (0.25 mg once daily) for 7 days did not alter the steady-state pharmacokinetics of digoxin.
Warfarin: In healthy volunteers, coadministration of pioglitazone (45 mg once daily) for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. In addition, pioglitazone has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy.
Metformin: In healthy volunteers, coadministration of metformin (1000 mg) and pioglitazone (45 mg) after 7 days of pioglitazone (45 mg once daily) did not alter the pharmacokinetics of the single dose of metformin.
Pioglitazone neither induced nor inhibited P450 activity when tested following chronic administration to rats or when incubated with human P450 liver microsomes indicating minimal effects of pioglitazone on metabolic pathways of the liver. The cytochrome P450 isoform CYP3A4 is partially responsible for the metabolism of pioglitazone. Specific formal pharmacokinetic interaction studies have not been conducted with pioglitazone and other drugs metabolized by this enzyme such as: erythromycin, astemizole, calcium channel blockers, cisapride, corticosteroids, cyclosporine, HMG-CoA reductase inhibitors, tacrolimus, trizolam, and trimetrexate, as well as inhibitory drugs such as ketoconazole and itraconazole. However, patients on drugs metabolized by cytochrome P450 enzymes including calcium channel blockers and HMG-CoA reductase inhibitors were permitted in clinical trials.
Adverse Effects: In worldwide clinical trials, over 3700 patients with type 2 diabetes have been treated with pioglitazone. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of pioglitazone monotherapy at doses of 7.5, 15, 30, or 45 mg once daily are shown in Table VI.
The types of clinical adverse events reported when pioglitazone was used in combination with sulfonylureas (N=373), metformin (N=168), or insulin (N=379) were generally similar to those reported during pioglitazone monotherapy with the exception of an increase in the occurrence of peripheral edema in the insulin combination study. This event was generally mild, resulting in only one patient withdrawing from the study.
Mild to moderate hypoglycemia was reported during combination therapy with sulfonylurea or insulin. Hypoglycemia was reported for 1% of placebo-treated patients and 2% of patients when pioglitazone was used in combination with a sulfonylurea. In combination with insulin, hypoglycemia was reported for 5% of placebo-treated patients, 8% for patients treated with 15 mg of pioglitazone, and 15% for patients treated with 30 mg of pioglitazone (see Precautions, General).
The incidence of withdrawals from clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or pioglitazone (3.3%). In all clinical trials weight increased proportionately as the HbA 1c decreased suggesting that weight gain was associated with improved glycemic control. However, excessive weight gain did result in 2 patients being withdrawn from the clinical trial.
Laboratory Abnormalities: Hematologic: Across all clinical studies, mean hemoglobin values declined by 2 to 4% in pioglitazone-treated patients. 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 not been associated with any significant hematologic clinical effects. Values remained within normal limits at all times (including up to 18 months of continuous therapy).
Serum Transaminase Levels: A total of 4 of 1526 (0.26%) pioglitazone-treated patients and 2 of 793 (0.25%) placebo-treated patients had ALT values ³3 times the ULN in double-blind, randomized clinical trials. During all clinical studies in the U.S., 11 of 2561 (0.43%) pioglitazone-treated patients had ALT values ³3 times the ULN. 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 0.12% of pioglitazone-treated patients were withdrawn from clinical trials due to abnormal liver function tests.
In preapproval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure.
Overdose: Symptoms: During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg/day for 4 days, then 180 mg/day for 7 days. The patient denied any clinical symptoms during this period.
Treatment: In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms.
Dosage: 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 FBG alone. HbA 1c reflects glycemia over the past 2 to 3 months. In clinical use, it is recommended that patients be treated with pioglitazone for a period of time adequate to evaluate change in HbA 1c unless glycemic control deteriorates.
Pioglitazone should be taken once daily without regard to meals.
Pioglitazone in patients not adequately controlled with diet and exercise may be initiated at 15 or 30 mg once daily. For patients who respond inadequately to the initial dose, the dose can be increased in increments up to 45 mg once daily.
The dose should not exceed 45 mg once daily since doses higher than 45 mg once daily have not been studied in placebo-controlled clinical studies.
Liver enzymes should be checked prior to the initiation of therapy with pioglitazone in all patients. Therapy with pioglitazone should not be initiated if a patient exhibits clinical evidence of liver disease or increased serum transaminase levels (ALT >2.5 times ULN). See Precautions, Hepatic Disease for additional information on liver enzyme monitoring. In cases where therapy is to be initiated, dose adjustment in patients with hepatic disease is not required (see Pharmacology, Special Populations, Hepatic Insufficiency).
Dose adjustment in patients with renal insufficiency is not required (see Pharmacology, Special Populations, Renal Insufficiency).
Information for the Patient: See Blue Section--Information for the Patient Actos.
Supplied: 15 mg: Each white to off-white, round, convex, non-scored tablet, with ACTOS printed on one side and 15 on the other, contains: pioglitazone HCl 15 mg. Nonmedicinal ingredients: carboxymethylcellulose calcium, hydroxypropylcellulose, lactose monohydrate and magnesium stearate. Bottles of 90.
30 mg: Each white to off-white, round, flat, non-scored tablet, with ACTOS printed on one side and 30 on the other, contains: pioglitazone HCl 30 mg. Nonmedicinal ingredients: carboxymethylcellulose calcium, hydroxypropylcellulose, lactose monohydrate and magnesium stearate. Bottles of 90.
45 mg: Each white to off-white, round, flat, non-scored tablet, with ACTOS printed on one side and 45 on the other, contains: pioglitazone HCl 45 mg. Nonmedicinal ingredients: carboxymethylcellulose calcium, hydroxypropylcellulose, lactose monohydrate and magnesium stearate. Bottles of 90.
Store at controlled room temperature (15 to 30°C) for up to 2 years. Keep container tightly closed and protect from moisture and humidity.
IMPORTANT NOTE: THE FOLLOWING INFORMATION IS INTENDED TO SUPPLEMENT, NOT SUBSTITUTE FOR, THE EXPERTISE AND JUDGMENT OF YOUR PHYSICIAN, PHARMACIST OR OTHER HEALTHCARE PROFESSIONAL. IT SHOULD NOT BE CONSTRUED TO INDICATE THAT USE OF THE DRUG IS SAFE, APPROPRIATE, OR EFFECTIVE FOR YOU. CONSULT YOUR HEALTHCARE PROFESSIONAL BEFORE USING THIS DRUG.
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