Actosmet

Actosmet

pioglitazone + metformin

Manufacturer:

Takeda
Full Prescribing Info
Contents
Pioglitazone HCl, metformin HCl.
Description
Each tablet contains pioglitazone hydrochloride 15 mg and metformin hydrochloride 850 mg.
Actosmet tablets contain 2 oral antihyperglycemic drugs used in the management of type 2 diabetes: Pioglitazone hydrochloride and metformin hydrochloride. The concomitant use of pioglitazone and metformin has been previously approved based on clinical trials in patients with type 2 diabetes inadequately controlled on metformin. Additional efficacy and safety information about pioglitazone and metformin monotherapies may be found in the prescribing information for each individual drug.
Pioglitazone hydrochloride is an oral antihyperglycemic agent that acts primarily by decreasing insulin resistance. Pioglitazone is used in the management of type 2 diabetes. Pharmacological studies indicate that pioglitazone improves sensitivity to insulin in muscle and adipose tissue, and inhibits hepatic gluconeogenesis. Pioglitazone 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, biguanides, or the α-glucosidase inhibitors. The molecule contains 1 aymmetric center, and the synthetic compound is a racemate. The 2 enantiomers of pioglitazone interconvert in vivo.
Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of C19H20N2O3S·HCl and molecular weight of 392.9. 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.
Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin hydrochloride is a white crystalline powder with a molecular formula of C4H11N5·HCl and molecular weight of 165.62. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.
Action
Pharmacology: Mechanism of Action: Actosmet combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with the type 2 diabetes: Pioglitazone hydrochloride, a member of the thiazolidinedione class, and metformin hydrochloride, a member of the biguanide class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.
Pioglitazone Hydrochloride: Pioglitazone depends on the presence of insulin for its metabolism of action. Piolitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal, and decreased hepatic glucose output. Unlike sulfonylureas, piogltiazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-γ (PPARγ). PPAR receptors are found in tissues important for insulin action eg, adipose tissue, skeletal muscle and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.
In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia and hypertriglyceridemia characteristic of insulin-resistant states eg, 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 endogeous insulin.
Metformin Hydrochloride: Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreased hepatic glucose production, decreased intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see General: Metformin Hydrochloride under Precautions) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Pharmacodynamics: Clinical Effects: Pioglitazone Hydrochloride: 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 plasma glucose concentrations, lower plasma insulin levels, and lower HbA1c values. Based on results from an open-label extension study, the glucose-lowering effects of pioglitazone appear to persist for at least 1 year. In controlled clinical studies, pioglitazone in combination with metformin had an additive effect on glycemic control.
Patients with lipid abnormalities were included in placebo-controlled monotherapy clinical studies with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in triglycerides, mean increases in HDL-cholesterol, and no consistent mean changes in LDL-cholesterol and total cholesterol compared to the placebo group. A similar pattern of results was seen in 16- and 24-week combination therapy studies of pioglitazone with metformin.
Pharmacokinetics: Absorption and Bioavailability: In bioequivalence studies of Actosmet 15 mg/850 mg, the area under the curve (AUC) and maximum concentration (Cmax) of both the pioglitazone and the metformin component following a single dose of the combination tablet were bioequivalent to Actos 15 mg concomitantly administered with metformin hydrochloride 850-mg tablet under fasted conditions in healthy subjects (see Table 1).


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Administration of Actosmet 15 mg/850 mg with food resulted in no change in overall exposure of pioglitazone. With metformin there was no change in AUC, however mean peak serum concentration of metformin was decreased by 28% when administered with food. A delayed time to peak serum concentration was observed for both components (1.9 hrs for pioglitazone and 0.8 hrs for metformin) under fed conditions. These changes are not likely to be clinically significant.
Pioglitazone Hydrochloride: Following oral administration, in the fasting state, pioglitazone is 1st measurable in serum within 30 min, with peak concentrations observed within 2 hrs. Food slightly delays the time to peak serum concentration to 3-4 hrs, but does not alter the extent of absorption.
Metformin Hydrochloride: The absolute bioavailabifity of a metformin 500-mg tablet given under fasting conditions is approximately 50 or 60%. Studies using single oral doses of metformin tablets of 500 mg to 1500 mg and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.
Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration, a 25% lower AUC in plasma concentration versus time curve and a 35 min prolongation of time to peak plasma concentration following administration of a single 850-mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Distribution: Pioglitazone Hydrochloride: The mean apparent volume of distribution (V/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.
Metformin Hydrochloride: The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24-48 hrs and are generally <1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.
Metabolism, Elimination and Excretion: Pioglitazone Hydrochloride: 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 30-50% of the total peak serum concentrations and 20-25% of the total AUC.
In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P4-50 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Precautions and Interactions: Pioglitazone Hydrochloride). Urinary 6β-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.
Following oral administration, approximately 15-30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted primarily as metabolites and the 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 3-7 hrs and 16-24 hrs, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5-7 L/hr.
Metformin Hydrochloride: IV single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance (CrCl) which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hrs, with a plasma elimination half-life of approximately 6.2 hrs. In blood, the elimination half-life is approximately 17.6 hrs, suggesting that the erythrocyte mass may be a compartment of distribution.
Special Populations: Renal Insufficiency: Pioglitazone Hydrochloride: The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (CrCl 30-60 mL/min) to severe (CrCl <30 mL/min) renal impairment when compared to normal subjects.
Metformin Hydrochloride: In patients with decreased renal function (based on CrCl), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in CrCl (see Clinical Effects and Pharmacokinetics: Metformin Hydrochloride under Actions, Contraindications and Warnings). Since metformin is contraindicated in patients with renal impairment, Actosmet is also contraindicated in these patients.
Hepatic Insufficiency: Pioglitazone Hydrochloride: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values.
Therapy with Actosmet should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal (see General: Pioglitazone Hydrochloride under Precautions).
Metformin Hydrochloride: No pharmacokinetic studies of metformin have been conducted in subjects with hepatic insufficiency.
Elderly: Pioglitazone Hydrochloride: 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.
Metformin Hydrochloride: Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
Actosmet treatment should not be initiated in patients ≥80 years unless measurement of creatinine clearance demonstrates that renal function is not reduced (see Dosage & Administration and Warnings).
Pediatrics: Pioglitazone Hydrochloride: Pharmacokinetic data in the pediatric population are not available. Use in pediatric patients is not recommended for the treatment of diabetes due to lack of long-term safety data. Risks including fractures and other adverse effects associated with pioglitazone, one of the components of Actosmet, have not been determined in this population (see Warnings and Precautions).
Metformin Hydrochloride: After administration of a single oral metformin 500-mg tablet with food, geometric mean metformin Cmax and AUC differed <5% between pediatric type 2 diabetic patients (12-16 years) and gender- and weight-matched healthy adults (20-45 years), and all with normal renal function.
Gender: Pioglitazone Hydrochloride: As monotherapy and in combination with sulfonylurea, metformin, or insulin, pioglitazone improved glycemic control in both males and females. The mean C max and AUC values were increased 20-60% in females. In controlled clinical trials, decreases from baseline in HbA1c were generally greater for females than for males (average mean difference in HbA1c 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.
Metformin Hydrochloride: Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
Ethnicity: Pioglitazone Hydrochloride: Pharmacokinetic data among various ethnic groups are not available.
Metformin Hydrochloride: No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51) and Hispanics (n=24).
Drug-Drug Interactions: Co-administration of a single dose of metformin (1000 mg) and pioglitazone after 7 days of pioglitazone (45 mg) did not alter the pharmacokinetics of the single dose of metformin. Specific pharmacokinetic drug interaction studies with Actosmet have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.
Pioglitazone Hydrochloride: The following drugs were studied in healthy volunteers with co-administration of pioglitazone 45 mg once daily. Results are listed as follows: Oral Contraceptives: Co-administration of pioglitazone (45 mg once daily) and an oral contraceptive (norethindrone 1 mg plus ethinyl estradiol 0.035 mg once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC(0-24 hr) and Cmax respectively. There were no significant changes in norethindrone AUC(024 hr) and Cmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown.
Midazolam: Administration of pioglitazone for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC.
Nifedipine ER: Co-administration of pioglitazone for 7 days with nifedipine ER 30 mg administered orally once daily for 4 days to male and female volunteers resulted in a ratio of least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73-0.95) for Cmax and 0.88 (0.8-0.96) for AUC. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.
Ketoconazole: Co-administration of pioglitazone for 7 days with ketoconazole 200 mg administered twice daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06-1.23) for Cmax, 1.34 (1.26-1.41) for AUC and 1.87 (1.71-2.04) for Cmin.
Atorvastatin Calcium: Co-administration of pioglilazone for 7 days with atorvastatin calcium (Lipitor) 80 mg once daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 0.69 (0.57-0.85) for Cmax, 0.76 (0.65-0.88) for AUC and 0.96 (0.87- 1.05) for Cmin. For unchanged atorvastatin the ratio of least square mean (90% CI) values were 0.77 (0.66-0.9) for Cmax, 0.86 (0.78-0.94) for AUC and 0.92 (0.82-1.02) for Cmin.
Cytochrome P-450: See Precautions and Interactions: Pioglitazone Hydrochloride.
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 (AUC0-24 hr) being 226% of the pioglitazone exposure in the absence of gemfibrozif (see Precautions and Interactions: Pioglitazone Hydrochloride).
Rifampin: Concomitant administration of rifampin (oral 600 mg once daily), an inducer of CYP2CB with pioglitazone (oral 30 mg) in 10 healthy volunteers pretreated for 5 days prior with rifampin (oral 600 mg once daily) resulted in a decrease in the AUC of pioglitazone by 54% (see Precautions and Interactions: Poglitazone Hydrochloride).
In other drug-drug interaction studies, pioglitazone had no significant effect on the pharmacokinetics of fexofenadine, glipizide, digoxin, warfarin, ranitidine hydrochloride or theophylline.
Metformin Hydrochloride: See Precautions and Interactions: Metformin Hydrochloride.
Toxicology: Animal Toxicity: Pioglitazone Hydrochloride: Heart enlargement has been observed in mice (100 mg/kg), rats (≥4 mg/kg) and dogs (3 mg/kg) treated orally with the pioglitazone hydrochloride component of Actosmet (approximately 11, 1 and 2 times the maximum recommended human oral dose for mice, rats and dogs, respectively, based on mg/m2). In a 1-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg daily (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 (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).
Indications/Uses
Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and metformin, or who have inadequate glycemic control on a thiazolidinedione alone or metformin alone.
Dosage/Direction for Use
General: The use of Actosmet in the management of type 2 diabetes should be individualized on the basis of effectiveness and tolerability.
Dosage Recommendations: Usual Starting Dose: 15 mg/850 mg once or twice daily with food to reduce the gastrointestinal side effects associated with metformin.
After initiation of Actosmet or with dose increase, patients should be carefully monitored for adverse events related to fluid retention (see Warnings).
The dosage of Actosmet should be gradually titrated, as needed, based on the adequacy of the therapeutic response.
Maximum Daily Dose: 45 mg/2550 mg of pioglitazone/metformin. This maximal dosage should be administered in divided doses with meals.
No studies have been performed specifically examining the safety and efficacy of Actosmet in patients previously treated with other oral hypoglycaemic agents and switched to Actosmet. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.
Sufficient time should be given to assess adequacy of therapeutic response. Ideally, the response to therapy should be evaluated using HbA1c, which is a better indicator of long-term glycemic control than FPG alone. HbA1c reflects glycemia over the past 2-3 months. In clinical use, it is recommended that patients be treated with Actosmet for a period of time adequate to evaluate change in HbA1c (8-12 weeks) unless glycemic control as measured by FPG deteriorates.
Overdosage
Pioglitazone Hydrochloride: During controlled clinical trials, 1 case of overdosage with pioglitazone was reported. A male patient took 120 mg daily for 4 days, then 180 mg daily for 7 days. The patient denied any clinical symptoms during this period.
In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms.
Metformin Hydrochloride: Overdosage of metformin hydrochloride has occurred, including ingestion of amounts >50 g. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdosage cases (see Metformin Hydrochloride under Warnings). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated metformin from patients in whom metformin overdosage is suspected.
Contraindications
Hypersensitivity to the pioglitazone hydrochloride and metformin hydrochloride or to any of the excipients of Actosmet.
Cardiac failure or history of cardiac failure (NYHA stages I to IV); acute or chronic disease which may cause tissue hypoxia eg, cardiac or respiratory failure, recents myocardial infarction, shock; hepatic impairment; acute alcohol intoxication, alcoholism; diabetic ketoacidosis or diabetic pre-coma; renal failure or renal dysfunction (creatinine clearance <60 mL/min). Acute conditions with the potential to alter renal function eg, dehydration, severe infection, shock, intravascular administration of iodinated contrast agents (see Warning and Precautions). Current bladder cancer or a history of bladder cancer.
Use in pregnancy: Pregnancy Category C: No preclinical or clinical data on exposed pregnancies or lactation are available.
Risk Related to Pioglitazone: There are no adequate human data from the use of pioglitazone in pregnant women. Animal studies have not shown teratogenic effects but have shown foetoxicity related to the pharmacologic action (see Toxicology under Actions).
Risk Related to Metformin: Animal studies have not revealed teratogenic effects. Small clinical trials have not revealed metformin to have malformative effects.
However, Actosmet should not be used during pregnancy and in women of childbearing age not using contraceptive measures. If a patient wishes to become pregnant or if a pregnancy occurs, treatment with Actosmet should be discontinued.
Both pioglitazone and metformin have been shown to be present in the milk of lactating rats. It is not known whether breast-feeding will lead to exposure of the infant to the medicinal product.
Actosmet must therefore not be used in women who are pregnant and breast-feeding (see Contraindications).
Use in lactation: No studies have been conducted with the combined components of Actosmet. In studies performed with the individual components, both pioglitazone and metformin are secreted in the milk of lactating rats. It is not known whether pioglitazone and/or metformin is secreted in human milk.
Because many drugs are excreted in human milk, Actosmet should not be administered to a breastfeeding woman. If Actosmet is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Warnings
Congestive Heart Failure: Thiazolidinediones, including pioglitazone, which is a component of Actosmet, cause or exacerbate congestive heart failure in some patients (see Pioglitazone Hydrochloride as follows). After initiation of Actosmet 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 Actosmet must be considered.
Actosmet is not recommended in patients with symptomatic heart failure. Initiation of Actosmet in patients with established NYHA Class III or IV heart failure is contraindicated (see Contraindications and Pioglitazone Hydrochloride as follows).
Lactic Acidosis: Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation. The risk increases with conditions eg, sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms eg, malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate. If acidosis is suspected, Actosmet should be discontinued and the patient hospitalized immediately (see texts as follows).
Metformin Hydrochloride: Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Actosmet (pioglitazone hydrochloride and metformin hydrochloride) tablets; when it occurs, it is falal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In >20,000 patient-years exposure 10 metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients ≥80 years unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see General: Metformin Hydrochloride under Precautions).
The onset of lactic acidosis often is subtle and accompanied only by nonspecific symptoms eg, malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see General: Metformin Hydrochloride under Precautions). Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal but <5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms eg, poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling (see General: Metformin Hydrochloride under Precautions).
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery (see Contraindications and General: Metformin Hydrochloride under Precautions).
Pioglitazone Hydrochloride: Fluid Retention and Cardiac Failure: Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure. When treating patients who have at least one risk factor for development of congestive heart failure (eg, prior myocardial infarction or symptomatic coronary artery disease), physicians should start with the lowest available dose and increase the dose gradually. Patients should be observed for sign and symptoms of heart failure, weight gain or edema particularly those with reduced cardiac reserve. There have been cases of cardiac failure reported from the market when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure. Therefore Actos is contraindicated in combination with insulin. Since NSAID and Actos are associated with fluid retention, concomitant administration may increase the risk of oedema. Pioglitazone should be discontinued if any deterioration in cardiac status occurs.
Monitoring of Liver Function: There have been rare report of hepatocellular dysfunction during post-marketing experience. It is recommended, therefore, 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. Therapy with pioglitazone should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5 x upper limit of normal) or with any other evidence of liver. Following initiation of therapy with pioglitazone, it is recommended that liver enzymes be monitored periodically based on clinical judgment. If ALT levels are increased to 3x upper limit of normal during pioglitazone therapy, liver enzymes should be reassessed as soon as possible. If ALT levels remain >3x the upper limit of normal, therapy should be discontinued. If any patients develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decisions whether to continue the patients on therapy with pioglitazone should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.
Weight Gain: In clinical trials with pioglitazone there was evidence of dose related weight gain, which may be due to fat accumulation and in some cases associated with fluid retention. In some cases weight increases may be a symptoms of cardiac failure, therefore weight should be closely monitored. Part of the treatment of diabetes is dietary control. Patients should be advised to adhere strictly to a calorie-controlled diet.
Haematology: There was a small reduction in haemoglobin (4% relative reduction) and in haematocrit (4.1% relative reduction) during therapy with pioglitazone, consistent with haemodilution. Similar changes were seen in metformin (haemoglobin 3-4% and haematocrit 3.6-4.1% relative reduction) and to a lesser extent sulfonylurea (haemoglobin 1-2% and haematocrit 1-3.2% relative reduction) treated patients in comparative controlled trials with pioglitazone. Actosmet may cause decreased in hemoglobin and hematocrit.
Hypoglycaemia: As a consequence of increased insulin sensitivity, patients receiving pioglitazone in dual or triple oral therapy with a sulphonylurea may be at risk for dose-related hypoglycaemia and a reduction in the dose of the sulphonylurea may be necessary.
Eye Disorders: Post-marketing reports of new-onset or worsening diabetic macular edema with decreased visual aculity have been been reported with thiazolidinediones, including pioglitazone. Many of these patients reported concurrent peripheral edema. It is unclear whether or not there is a direct association between pioglitazone and macular edema but prescribers should be alert to the possibility of macular edema if patients report disturbances in visual acuity; an appropriate opthalmological referral should be considered.
Others: An increased incidence in bone fractures in women was seen in a pooled analysis of adverse events reports of bone fractures from randomized, controlled, double-blind clinical trials in over 8100 pioglitazone and 7400 comparator treated patients, on treatment for up to 3.5 years.
Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated with a comparator. No increase in fracture reates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).
The fracture incidence calculated was 1.9 fracture/100 patient-years in women treated with pioglitazone and 1.1 fracture/100 patient-years in women treated with comparator. The observed excess risk of fractures for women in this dataset on pioglitazone in therefore 0.8 fractures/100 patient-years of use.
In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1 fractures/100 patient-years) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures/100 patient-years) of female patients treated with comparator. No increased in fracture rates was observed in men treated with pioglitazone.
As a consequences of enhancing insulin action, pioglitazone treatment in patients with polycystic ovarian syndrome may result in resumption of ovulation. These patients may be risk of pregnancy.
Patients should be aware of the risk of pregnancy and if a patients wishes to become pregnant or if pregnancy occurs the treatment should be discontinued.
Pioglitazone should be used with caution during concomitant administration of cytochrome be monitored closely. Pioglitazone dose adjustment within the recommended posology or changes in diabetic treatment should be considered.
The tablets contain lactose monohydrate and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption.
Metformin: Monitoring of Renal Function and Concomitant Use with Other Medications that may Affect Renal Function: Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increase proportionally with the degree of impairment of renal function. Patients with serum creatinine levels above the upper limit of normal value for their age should not receive Actosmet. In patients with advanced age, actosmet should be carefully titrated, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years, therapy with Actosmet is not recommended, except creatinine clearance measurement shows no reduced renal function.
In patients whose development of renal dysfunction is anticipated, renal function should be assessed more frequently and Actosmet should be discontinued if evidence of renal impairment is present.
Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin eg, cationic drugs that are eliminated by renal tubular secretion, should be used with caution. The used of IV iodinated contrast materials can lead to acute alteration of renal function and lactic acidosis in patients receiving Actosmet. Therefore, for patients who will undergo such procedure, Actosmet should be temporary discontinued at the time of or prior to the procedure, and should not given in the next 48 hrs and may be reinstituted only after renal function has been reevaluated and found to be normal.
Hipoxic States: Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may cause pre-renal azotemia. Therapy should be discontinued promptly when such events occur in patients receiving Actosmet.
Surgery: Therapy with Actosmet should be temporary suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids), and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
Alcohol Intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Actosmet.
Impaired Hepatic Function: Since impaired hepatic function has been associated with some cases of lactic acidosis, Actosmet should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 Levels: In controlled clinical trials of metformin at 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12 intrinsic factor complex, is however very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis in advised in patients on Actosmet and any apparent abnormalities should be appropriately investigated and predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2-3 year intervals may be useful.
Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes: In patients with type 2 diabetes previously well controlled on Actosmet who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should be include serum electrolytes and ketones, blood glucose, and if indicated, blood PH, lactate pyruvate and metformin levels. If acidosis of either form accurs, Actosmet must be stopped immediately and other appropriate corrective measure initiated (see Metformin Hydrochloride as previously mentioned).
Laboratory Test: FPG and A1C measurements should be performed periodically to monitor glycemic control and therapeutic response to Actosmet.
Liver enzyme monitoring us recommended prior to initiation of therapy with Actosmet in all patients and periodically thereafter per the clinical judgment of the healthcare professional (see General: Pioglitazone Hydrochloride under Precautions and Serum Transaminase Levels under Adverse Reactions).
Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cells indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, vitamin B12 deficiency should be excluded.
Special Precautions
Lactic Acidosis: Lactic acidosis is a very rare, but serious, metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors eg, poorly controlled diabetes, ketosis, plolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.
Diagnosis: Lactic acidosis is characterized by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels >5mmol/L, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment with the medicinal product should be discontinued and the patient hospitalised immediately (see Overdosage).
Renal Function: As metformin is excreted by the kidney, serum creatinine concentrations should be determined regularly at least once a year in patients with normal renal function or at least 2-4 times a year in patients with serum creatinine levels at the upper limits of normal and in elderly subjects.
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired ie, when initiating antihypertensive therapy or diuretic therapy and when starting treatment with a NSAID.
Surgery: As Actosmet contains metformin hydrochloride, the treatment should be discontinued 48 hrs before elective surgery with general anaesthesia and should not be usually resumed earlier than 48 hrs afterwards.
Administration of Iodinated Contrast Agent: The intravascular administration of iodinated contrast agents in radiological can lead discontinued prior to, or at the time of the test and not reinstituted until 48 hrs afterwards and only after renal function has been re-evaluated and found to be normal.
Polycystic Ovarian Syndrome: As a consequence of enhancing insulin action, pioglitazone treatment in patients with polycystic ovarian syndrome may result in resumption of ovulation. These patients may be at risk of pregnancy. Patients should be aware of the risk of pregnancy and if a patient wishes to become pregnant or if pregnancy occurs, the treatment should be discontinued.
Bladder Cancer: Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks include age, smoking history, exposure to some occupational or chemotherapy agents eg, cyclophosphamide or prior radiation treatment in the pelvic region).
Any macroscopic haematuria should be investigated before starting pioglitazone therapy. Patients should be advised to promptly seek the attention of the physician if macroscopic haematuria or other symptoms eg, dysuria or urinary urgency develop during treatment.
Patients who received pioglitazone more than 1 year, should be evaluated periodically for bladder cancer risk by urinalysis.
Information for Patients: Patients should be instructed regarding the importance of adhering to dietary instructions, a regular exercise program, and regular testing of blood glucose and HbA1c. During periods of stress eg, fever, trauma, infection or surgery, medication requirements may change, and patients should be reminded to seek medical advice promptly.
The risks of lactic acidosis, its symptoms and conditions that predispose to its development, as noted should be explained to patients. Patients should be advised to discontinue Actosmet immediately and to promptly notify the healthcare professional if unexplained hyperventilation, myalgia, malaise, unusual somnolence or other nonspecific symptoms occur.
Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of Actosmet therapy; however, patients should consult with the physician if they develop unexplained symptoms. Although gastrointestinal symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious disease.
Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving Actosmet. Patients who experience an unusually rapid increase in weight or edema, or who develop shortness of breath or other symptoms of heart failure while on Actosmet should immediately report these symptoms to the physician.
Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the healthcare professional.
Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia or dark urine.
Patients should be informed about the importance of regular testing of renal function and hematologic parameters when receiving treatment with Actosmet.
Therapy with a thiazolidinedione, which is the active pioglitazone component of the Actosmet tablet, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Actosmet. Thus, 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.
Combination antihyperglycemic therapy may cause hypoglycemia. When initiating Actosmet, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients.
Patients should be told to take Actosmet as prescribed and instructed that any change in dosing should only be done if directed by the physician. Patients should be informed that if a dose is missed, to take the next dose as prescribed unless directed otherwise by the physician. Patients should be informed that Actosmet must be swallowed whole and not chewed, cut or crushed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Actosmet: No animal studies have been conducted with Actosmet. The following data are based on findings in studies performed with pioglilazone or metformin individually.
Pioglitazone Hydrochloride: A 2-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 daily and above (approximately equal to the maximum recommended human oral dose based on mg/m2). A 2-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg daily (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 >1800 patients receiving pioglitazone 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 <1 year at the time of diagnosis of bladder cancer, there were 6 (0.16%) cases on pioglitazone and 2 (0.05%) on placebo.
Pioglitazone hydrochloride 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 pioglitazone hydrochloride 40 mg/kg daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m2).
Metformin Hydrochloride: Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg daily and 1500 mg/kg daily, respectively. These doses are both approximately 4 times a human daily dose of 2000 mg of the metformin component of Actosmet based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with melformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg daily.
There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells) or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg daily, which is approximately 3 times the maximum recommended human daily dose of the metformin component of Actosmet based on body surface area comparisons.
Use in children: Safety and effectiveness of Actosmet in pediatric patients have not been established. Use in pediatric patients is not recommended for the treatment of diabetes due to lack of long-term safety data. Risks including fractures and other adverse effects associated with pioglitazone, 1 of the components of Actosmet, have not been determined in this population (see Warnings).
Use in the elderly: Pioglilazone Hydrochloride: Approximately 500 patients in placebo-controlled clinical trials of pioglitazone were ≥65 years. No significant differences in effectiveness and safety were observed between these patients and younger patients.
Metformin Hydrochloride: Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Actosmet should only be used in patients with normal renal function (see Special Populations under Actions, Contraindications and Metformin Hydrochloride under Warnings). Because aging is associated with reduced renal function, Actosmet should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Actosmet (see Dosage & Administration and Metformin Hydrochloride under Warnings).
Use In Pregnancy & Lactation
Use in pregnancy: Pregnancy Category C: No preclinical or clinical data on exposed pregnancies or lactation are available.
Risk Related to Pioglitazone: There are no adequate human data from the use of pioglitazone in pregnant women. Animal studies have not shown teratogenic effects but have shown foetoxicity related to the pharmacologic action (see Toxicology under Actions).
Risk Related to Metformin: Animal studies have not revealed teratogenic effects. Small clinical trials have not revealed metformin to have malformative effects.
However, Actosmet should not be used during pregnancy and in women of childbearing age not using contraceptive measures. If a patient wishes to become pregnant or if a pregnancy occurs, treatment with Actosmet should be discontinued.
Both pioglitazone and metformin have been shown to be present in the milk of lactating rats. It is not known whether breast-feeding will lead to exposure of the infant to the medicinal product.
Actosmet must therefore not be used in women who are pregnant and breast-feeding (see Contraindications).
Use in lactation: No studies have been conducted with the combined components of Actosmet. In studies performed with the individual components, both pioglitazone and metformin are secreted in the milk of lactating rats. It is not known whether pioglitazone and/or metformin is secreted in human milk.
Because many drugs are excreted in human milk, Actosmet should not be administered to a breastfeeding woman. If Actosmet is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Adverse Reactions
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 and over 4500 patients for 1 year or longer. Over 3000 patients have received pioglitazone for at least 2 years.
The most common adverse events reported in at least 5% of patients in the controlled 16-week clinical trial between placebo plus metformin and pioglitazone 30 mg plus metformin were upper respiratory tract infection (15.6% and 15.5%), diarrhea (6.3% and 4.8%), combined edema/peripheral edema (2.5% and 6%) and headache (1.9% and 6%), 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 metformin, and pioglitazone 45 mg plus metformin are shown in Table 2; the rate of adverse events resulting in study discontinuation between the 2 treatment groups was 7.8% and 7.7%, respectively.


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Most clinical adverse events were similar between groups treated with pioglitazone in combination with metformin and those treated with pioglitazone monotherapy. Other adverse events reported in at least 5% of patients in controlled clinical trials 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 US, double-blind studies, anemia was reported in ≤2% of patients treated with pioglitazone plus metformin (see General: Piogliitazone Hydrochloride under Precautions).
In monotherapy studies, edema was reported for 4.8% (with doses from 7.5-45 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 General: Pioglitazone Hydrochloride under Precautions).
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 (β-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). 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.


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Post-marketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see General: Pioglitazone Hydrochloride under Precautions).
Laboratory Abnormalities: 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 4-12 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 General: Pioglitazone Hydrochloride under Precautions).
In controlled clinical trials of metformin at 29 weeks' duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation (see General: Metformin Hydrochloride under Precautions).
Serum Transaminase Levels: During all clinical studies in the US, 14 of 4780 (0.3%) 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, aspartate aminotransferace (AST), ALT, alkaline phosphatase, and γ-glutamyl transferase (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 US due to abnormal liver function tests.
In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see General: PiogJitazone Hydrochloride under Precautions).
Creatine Phosphokinase (CPK) Levels: During required laboratory testing in clinical trials with pioglitazone, sporadic, transient elevations in CPK levels were observed. An isolated elevation to >10 times the upper limit of normal was noted in 9 patients (values of 2150-11,400 IU/L). Six of these patients continued to receive pioglitazone, 2 patients had completed receiving study medication at the time of the elevated value and 1 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.
Drug Interactions
Pioglitazone Hydrochloride: In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP450 isoform 3A4 substrate.
An enzyme inhibitor of CYP2C8 (eg, gemfibrozil) may significantly increase the area under the concentration-time curve (AUC) of pioglitazone and an enzyme inducer of CYP2CB (eg, rifampin) may significantly decrease the AUC of piogJitazone. Therefore. if an inhibitor or inducer of CYP2CB is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response (see Drug-Drug Interactions: Pioglitazone Hydrochloride under Actions).
Metformin Hydrochloride: Glyburide: In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain.
Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22%, and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.
Nifedipine: A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Maximum plasma concentration (Tmax) and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
Cationic Drugs: Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies with a 60% increase in peak metformin plasma, and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Actosmet and/or the interfering drug is recommended in patients who are taking cationic  medications that are excreted via the proximal renal tubular secretory system.
Other: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium-channel blocking drugs and isoniazid. When such drugs are administered to a patient receiving Actosmet, the patient should be observed closely for hypoglycemia.
In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies.
Metformin is negligibly bound to plasma proteins and is therefore, less likely to interact with highly protein bound drugs eg, salicylates, sulfonamides, chloramphenicol and probenecid.
Storage
Store below 25°C. Protect from moisture and humidity.
MIMS Class
ATC Classification
A10BD05 - metformin and pioglitazone ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.
Presentation/Packing
FC tab 15/850 mg (white to off-white, oblong, with "4833M" on one side, and "15/850" on the other) x 2 x 7's.
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