Asenza Plus

Pioglitazone hydrochloride, glimepiride.

Each uncoated tablet contains: Pioglitazone (as hydrochloride), USP 15 mg; Glimepiride, USP 2 mg.
Pioglitazone (as hydrochloride), USP 30 mg; Glimepiride, USP 2 mg.

Blood Glucose Lowering Drugs Combination.
Pharmacology: Pharmacodynamics: Asenza Plus combines 2 anti-hyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: pioglitazone, a member of the thiazolidinedione class, and glimepiride, a member of the sulfonylurea class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas sulfonylureas are insulin secretagogues that act primarily by stimulating release of insulin from functioning pancreatic beta cells.
Pioglitazone: Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as 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 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.
Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
Glimepiride: Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic beta cells. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.
Pharmacokinetics: Pioglitazone: Absorption and Bioavailability: Following once-daily administration of pioglitazone, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within seven days. At steady-state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady-state, in both healthy volunteers and patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to 25% of the total AUC.
Cmax, AUC, and trough serum concentrations (Cmin) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.
Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours. Food delays Tmax to three to four hours but does not alter the extent of absorption (AUC).
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. M-III and M-IV are also 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-III and M-IV are the major circulating active metabolites in humans.
In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone which include CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo study of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor, showed that pioglitazone is a CYP2C8 substrate. Urinary 6β-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.
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 (t½) of pioglitazone and its metabolites (M-III and M-IV) range 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/hr.
Glimepiride: Absorption and Bioavailability: Studies with single oral doses of glimepiride in healthy subjects and with multiple oral doses in patients with type 2 diabetes showed peak drug concentrations (Cmax) two to three hours post-dose. When glimepiride was given with meals, the mean Cmax and AUC were decreased by 8% and 9%, respectively.
Glimepiride does not accumulate in serum following multiple dosing. The pharmacokinetics of glimepiride does not differ between healthy subjects and patients with type 2 diabetes. Clearance (CL/F) of glimepiride after oral administration does not change over the 1 mg to 8 mg dose range, indicating linear pharmacokinetics.
In healthy subjects, the intra- and inter-individual variabilities of glimepiride pharmacokinetic parameters were 15% to 23% and 24% to 29%, respectively.
Distribution: After intravenous (IV) dosing in healthy subjects, Vd/F was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.
Metabolism: Glimepiride is completely metabolized by oxidative biotransformation after either an IV or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). CYP2C9 is involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. In animals, M1 possesses about one-third of the pharmacological activity of glimepiride, but it is unclear whether M1 results in clinically meaningful effects on blood glucose in humans. M2 is inactive.
Excretion and Elimination: When 14C-glimepiride was given orally to three healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in seven days. M1 and M2 accounted for 80% to 90% of the radioactivity recovered in the urine. The ratio of M1 to M2 in the urine was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces. M1 and M2 accounted for approximately 70% (ratio of M1 to M2 was 1:3) of the radioactivity recovered in feces. No parent drug was recovered from urine or feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite was observed.

Pioglitazone/Glimepiride Tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and sulfonylurea or who have inadequate glycemic control on a thiazolidinedione alone or a sulfonylurea alone.
Important Limitations of Use: Pioglitazone exerts its anti-hyperglycemic effect only in the presence of endogenous insulin. Pioglitazone/Glimepiride Tablets should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. Use caution in patients with liver disease.

General: The use of anti-hyperglycemic therapy in the management of type 2 diabetes should be individualized on the basis of effectiveness and tolerability. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia.
Recommended Dose: Selecting the starting dose of Pioglitazone/Glimepiride Tablets should be based on the patient's current regimen of pioglitazone and/or sulfonylurea. Those patients who may be more sensitive to antihyperglycemic drugs should be monitored carefully during dose adjustment. It is recommended that a single dose of Pioglitazone/Glimepiride Tablets be administered once daily with the first main meal.
Patients Currently on Pioglitazone HCl Monotherapy: Usual Starting Dose: Glimepiride (1 or 2 mg once daily) and pioglitazone HCl 15 or 30 mg, Pioglitazone/Glimepiride Tablets may be initiated at 15 mg/2 mg once daily and adjusted after assessing adequacy of therapeutic response.
Patients Currently on Glimepiride Monotherapy: Usual Starting Dose: Pioglitazone HCl (15 or 30 mg daily), Pioglitazone/Glimepiride Tablets may be initiated at 15 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.
Patients Switching from Combination Therapy of Pioglitazone plus Glimepiride as Separate Tablets: May be initiated with 15 mg/2 mg tablet based on the dose of pioglitazone HCl and glimepiride already being taken. Patients who are not controlled with pioglitazone HCl 15 mg in combination with glimepiride should be carefully monitored when switched to Pioglitazone/Glimepiride Tablets.
Patients Currently on a Different Sulfonylurea Monotherapy or Switching from Combination Therapy of Pioglitazone Plus a Different Sulfonylurea: No exact dosage relationship exists between glimepiride and the other sulfonylurea agents. Therefore, based on the maximum starting dose of glimepiride 2 mg, Pioglitazone/Glimepiride Tablets should be limited initially to a starting dose of 15 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response. Any change in diabetic therapy should be undertaken with care and appropriate monitoring as change in glycemic control can occur. Patients should be observed carefully for hypoglycemia (1-2 weeks) when being transferred to Pioglitazone/Glimepiride Tablets, especially from longer t½ sulfonylureas due to potential overlapping of drug effect.
Maximum Recommended Dose: The maximum recommended daily dose for pioglitazone is 15 mg plus glimepiride 2 mg or a pioglitazone 30 mg plus glimepiride 4 mg formulation for oral administration.
Maximum Recommended Daily Dose: Pioglitazone is 45 mg and glimepiride is 8 mg. Pioglitazone/Glimepiride Tablets should therefore not be given more than once daily at any of the tablet strengths.
Elderly, Debilitated or Malnourished Patients, or in Patients with Renal or Hepatic Impairment: Initial dosing, dose increments, and maintenance dosage of Pioglitazone/Glimepiride Tablets should be conservative to avoid hypoglycemic reactions. These patients should be started at glimepiride 1 mg prior to prescribing Pioglitazone/Glimepiride Tablets.
During initiation of Pioglitazone/Glimepiride Tablets therapy and any subsequent dose adjustment, patients should be observed carefully for hypoglycemia.
Therapy with Pioglitazone/Glimepiride Tablets should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT >2.5 x ULN) at start of therapy.
The lowest approved dose of Pioglitazone/Glimepiride Tablets therapy should be prescribed to patients with type 2 diabetes and systolic dysfunction only after titration from pioglitazone HCl 15-30 mg has been safely tolerated. If subsequent dose adjustment is necessary, patients should be carefully monitored for weight gain, edema or signs and symptoms of congestive heart failure exacerbation.
Concomitant Use with an Insulin Secretagogue or Insulin: If hypoglycemia occurs in a patient co-administered Pioglitazone/Glimepiride Tablets and an insulin secretagogue, the dose of the insulin secretagogue should be reduced.
If hypoglycemia occurs in a patient co-administered Pioglitazone/Glimepiride Tablets and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.
Concomitant Use with Strong CYP2C8 Inhibitors: Co-administration of pioglitazone and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors. If gemfibrozil or other CYP2C8 inhibitors need to co-administered, patients should switch to individual components of Pioglitazone/Glimepiride Tablets because the minimum dose of pioglitazone in Pioglitazone/Glimepiride Tablets exceeds 15 mg.
Concomitant Use with Colesevelam: When colesevelam is co-administered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, Pioglitazone/Glimepiride Tablets should be administered at least four hours prior to colesevelam.
Pediatric Use: Safety and effectiveness of Pioglitazone/Glimepiride Tablets in pediatric patients have not been established.
Geriatric Use: To minimize the risk of hypoglycemia, the initial dosing, dose increments, and maintenance dosage of Pioglitazone/Glimepiride Tablets should be conservative. During initiation of Pioglitazone/Glimepiride Tablets therapy and any subsequent dose adjustments, geriatric patients should be observed carefully for hypoglycemia.
Renal Impairment: To minimize the risk of hypoglycemia, the initial dosing, dose increments and maintenance dosage of Pioglitazone/Glimepiride Tablets should be conservative. During initiation of Pioglitazone/Glimepiride Tablets therapy and any subsequent dose adjustments, these patients should be observed carefully for hypoglycemia.

Pioglitazone: During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.
In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.
Glimepiride: An overdosage of glimepiride, as with other sulfonylureas, can produce severe hypoglycemia. Mild episodes of hypoglycemia can be treated with oral glucose. Severe hypoglycemic reactions constitute medical emergencies requiring immediate treatment. Severe hypoglycemia with coma, seizure, or neurological impairment can be treated with glucagon or intravenous glucose.
Continued observation and additional carbohydrate intake may be necessary because hypoglycemia may recur after apparent clinical recovery.

Use in patients with known hypersensitivity to pioglitazone, glimepiride or any other component of the formulation.
Initiation in patients with established NYHA Class III or IV heart failure.
Use in patients with known history of an allergic reaction to sulfonamide derivatives.
Reported hypersensitivity reactions with glimepiride include cutaneous eruptions with or without pruritus as well as more serious reactions (e.g., anaphylaxis, angioedema, Stevens Johnson Syndrome, dyspnea).

Congestive Heart Failure: Pioglitazone: Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when Pioglitazone/Glimepiride Tablets are used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of this combination must be considered.
Hypoglycemia: Glimepiride: All sulfonylureas, including glimepiride, a component of this formulation, can cause severe hypoglycemia. The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death.
Patients must be educated to recognize and manage hypoglycemia. Use caution when initiating and increasing Pioglitazone/Glimepiride Tablets doses in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, and patients on other antidiabetic medications). Debilitated or malnourished patients and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of glucose-lowering medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested.
Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.
Hypersensitivity Reactions: Glimepiride: There have been post-marketing reports of hypersensitivity reactions in patients treated with glimepiride, a component of Pioglitazone/Glimepiride Tablets, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, promptly discontinue Pioglitazone/Glimepiride Tablets, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.
Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas: Glimepiride: The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups.
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2.5 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride tablets and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
Hepatic Effects: Pioglitazone: There have been post-marketing reports of fatal and non-fatal hepatic failure in patients taking pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone-controlled clinical trial database to date.
Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating Pioglitazone/Glimepiride Tablets therapy. In patients with abnormal liver tests, Pioglitazone/Glimepiride Tablets should be initiated with caution.
Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), Pioglitazone/Glimepiride Tablets treatment should be interrupted and investigation done to establish the probable cause. Pioglitazone/Glimepiride Tablets should not be restarted in these patients without another explanation for the liver test abnormalities.
Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury and should not be restarted on Pioglitazone/Glimepiride Tablets. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with Pioglitazone/Glimepiride Tablets can be used with caution.
Urinary Bladder Tumors: Pioglitazone: Pioglitazone may be associated with an increase in the risk of urinary bladder tumors. There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, Pioglitazone/Glimepiride Tablets should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with Pioglitazone/Glimepiride Tablets should be considered in patients with a prior history of bladder cancer.
Edema: Pioglitazone: Pioglitazone/Glimepiride Tablets should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Pioglitazone/Glimepiride Tablets should be used with caution in patients at risk for congestive heart failure. Patients treated with Pioglitazone/Glimepiride Tablets should be monitored for signs and symptoms of congestive heart failure.
Fractures: Pioglitazone: The risk of fracture should be considered in the care of patients, especially female patients, treated with Pioglitazone/Glimepiride Tablets and attention should be given to assessing and maintaining bone health according to current standards of care.
Hemolytic Anemia: Glimepiride: Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because Pioglitazone/Glimepiride Tablets contain glimepiride, which belongs to the class of sulfonylurea agents, use caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative. There are also post-marketing reports of hemolytic anemia in patients receiving glimepiride who did not have known G6PD deficiency.
Macular Edema: Pioglitazone: Macular edema has been reported in post-marketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.
Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione.
Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings.
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Pioglitazone/Glimepiride Tablets.

Pregnancy: Limited data with Pioglitazone/Glimepiride Tablets or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are clinical considerations related to fetal and neonatal adverse reactions and drug discontinuation if glimepiride is used during pregnancy. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.
Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, Pioglitazone/Glimepiride Tablets should be discontinued at least two weeks before expected delivery.
Lactation: There is no information regarding the presence of pioglitazone or glimepiride in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone and glimepiride are present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Pioglitazone/Glimepiride Tablets and any potential adverse effects on the breastfed infant from Pioglitazone/Glimepiride Tablets or from the underlying maternal condition.

Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The adverse events reported in at least 5% of patients in the controlled 16-week clinical studies between placebo plus a sulfonylurea and pioglitazone (15 mg and 30 mg combined) plus sulfonylurea treatment arms were upper respiratory tract infection (15.5% and 16.6%), accidental injury (8.6% and 3.5%), and combined edema/peripheral edema (2.1% and 7.2%), 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 a sulfonylurea and pioglitazone 45 mg plus a sulfonylurea are shown in the table; the rate of adverse events resulting in study discontinuation between the two treatment groups was 6% and 9.7%, respectively. (See table.)

Click on icon to see table/diagram/image

Pioglitazone: New onset or worsening diabetic macular edema with decreased visual acuity.
Fatal and nonfatal hepatic failure.
Post marketing reports of congestive heart failure have been reported in patients treated with pioglitazone, both with and without previously known heart disease and both with and without concomitant insulin administration.
In post marketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure.
Glimepiride: Serious hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome.
Hemolytic anemia in patients with and without G6PD deficiency.
Impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may progress to liver failure.
Porphyria cutanea tarda, photosensitivity reactions and allergic vasculitis.
Leukopenia, agranulocytosis, aplastic anemia, and pancytopenia.
Thrombocytopenia (including severe cases with platelet count less than 10,000/mcL) and thrombocytopenic purpura.
Hepatic porphyria reactions and disulfiram-like reactions.
Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH), most often in patients who are on other medications or who have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone.

Pioglitazone: Strong CYP2C8 Inhibitors: An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t½) of pioglitazone. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors. Since the minimum dose of pioglitazone in Pioglitazone/Glimepiride Tablets exceeds 15 mg, patients taking concomitant strong CYP2C8 inhibitors should switch to individual components of Pioglitazone/Glimepiride Tablets, unless the prescribing health care provider determines that the benefit of Pioglitazone/Glimepiride Tablets clearly outweighs the risk of increased pioglitazone exposure.
CYP2C8 Inducers: An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for pioglitazone.
Topiramate: A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate. The clinical relevance of this decrease is unknown; however, when Pioglitazone/Glimepiride Tablets and topiramate are used concomitantly, monitor patients for adequate glycemic control.
Glimepiride: Drugs Affecting Glucose Metabolism: A number of medications affect glucose metabolism and may require Pioglitazone/Glimepiride Tablets dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control.
The following are examples of medications that may increase the glucose-lowering effect of sulfonylureas including glimepiride, a component of this formulation, increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors. When these medications are administered to a patient receiving Pioglitazone/Glimepiride Tablets, monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving Pioglitazone/Glimepiride Tablets, monitor the patient closely for worsening glycemic control.
The following are examples of medications that may reduce the glucose-lowering effect of sulfonylureas including glimepiride, leading to worsening glycemic control: danazol, glucagon, somatropin, protease inhibitors, atypical antipsychotic medications (e.g., olanzapine and clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid. When these medications are administered to a patient receiving Pioglitazone/Glimepiride Tablets, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving Pioglitazone/Glimepiride Tablets, monitor the patient closely for hypoglycemia.
Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of this formulation's glucose-lowering effect.
Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of Pioglitazone/Glimepiride Tablets in an unpredictable fashion.
The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.
Miconazole: A potential interaction between oral miconazole and sulfonylureas leading to severe hypoglycemia has been reported. Whether this interaction also occurs with other dosage forms of miconazole is not known.
CYP2C9 Interactions: There may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers (e.g., rifampin) of CYP2C9. Fluconazole may inhibit the metabolism of glimepiride, causing increased plasma concentrations of glimepiride which may lead to hypoglycemia. Rifampin may induce the metabolism of glimepiride, causing decreased plasma concentrations of glimepiride which may lead to worsening glycemic control.
Concomitant Administration of Colesevelam: Colesevelam can reduce the maximum plasma concentrations and total exposure of glimepiride when the two are co-administered. However, absorption is not reduced when glimepiride is administered four hours prior to colesevelam. Therefore, Pioglitazone/Glimepiride Tablets should be administered at least four hours prior to colesevelam.

Store at temperatures not exceeding 30°C.

Antidiabetic Agents

A10BD06 - glimepiride and pioglitazone ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.

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