FORMULATION
Each film coated tablet contains:
Pioglitazone (as hydrochloride) ……… 15mg
Metformin (as hydrochloride) ……… 500mg
Glimepiride ……… 1mg
Each film coated tablet contains:
Pioglitazone (as hydrochloride) ……… 15mg
Metformin (as hydrochloride) ……… 850mg
Glimepiride ……… 1mg
Each film coated tablet contains:
Pioglitazone (as hydrochloride) ……… 15mg
Metformin (as hydrochloride) ……… 500mg
Glimepiride ……… 2mg
Each film coated tablet contains:
Pioglitazone (as hydrochloride) ……… 15mg
Metformin (as hydrochloride) ……… 850mg
Glimepiride ……… 2mg
INDICATIONS
As second-line therapy when diet, exercise, and the single agents or dual therapy do not result in adequate glycemic control in patients with Type 2 diabetes (non-insulin dependent diabetes mellitus)
CONTRA-INDICATIONS
Hypersensitivity to pioglitazone, metformin or glimepiride; cardiac failure or history of cardiac failure (NYHA stages I to IV); acute or chronic disease which may cause tissue hypoxia (i.e., cardiac or respiratory failure, recent myocardial infarction, shock); hepatic impairment; acute alcohol intoxication or 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 (i.e., dehydration, severe infection, shock, intravascular administration of iodinated contrast agents); pregnancy; lactation.
DOSAGE AND ADMINSTRATION
Adults: The dosage should be individualized on the basis of both effectiveness and tolerability while not exceeding the maximum recommended daily dose of glimepiride (8 mg); pioglitazone (45 mg) and metformin (2550 mg). The recommended starting dose is one tablet containing pioglitazone 15mg plus metformin 500mg plus glimepiride 1mg, once daily with a meal. The dose may then be titrated upwards based on response and patient tolerability to pioglitazone 15mg plus metformin 500mg plus glimepiride 1mg or pioglitazone 15mg plus metformin 850mg plus glimepiride 1mg twice or thrice daily. Or as prescribed by the physician.
Elderly: Renal function in the elderly is reduced. The recommended staring dose is pioglitazone 15mg plus metformin 500mg plus glimepiride 1mg. The dose should then be titrated according to the patients’ response and tolerability to treatment. Renal function should be monitored regularly. Or as prescribed by the physician.
Patients with renal Impairment: The combination should not be used in patients with renal failure or renal dysfunction (creatinine clearance <60 ml/min).
Patients with hepatic disease
The combination should not be used in patients with hepatic impairment.
Children and Adolescents: There is no data available on the use of the combination in patients under the age of 18 years. Therefore the use of the combination in this age group is not recommended.
PHARMACOLOGY
The combination contains three oral anti-hyperglycemic drugs commonly used to lower blood glucose levels; glimepiride, pioglitazone and metformin. Glimepiride lowers blood glucose levels by enhancing the secretion of insulin from functioning pancreatic beta cells lowering blood glucose levels. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARy). PPARy receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscles and liver. Activation of PPARy nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. Pioglitazone requires 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. Metformin lowers both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia. Metformin may act via three mechanisms: by reducing hepatic glucose production via inhibition of gluconeogenesis and glycogenolysis, modestly increasing skeletal muscle insulin sensitivity thereby improving peripheral glucose uptake and utilization, delaying intestinal glucose absorption. In humans, independently of its action on glycemia, metformin has favorable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term and long-term clinical studies: metformin reduces total cholesterol, LDL-C and triglyceride levels.
PHARMACOKINETICS
Glimepiride
Absorption: After oral administration, glimepiride is completely (100%) absorbed from the GI tract. Studies with single oral doses in normal subjects and with multiple oral doses in patients with Type 2 diabetes have shown significant absorption of glimepiride within 1 hour after administration and peak drug levels (C max) at 2 to 3 hours. When glimepiride was given with meals, the mean T max was slightly increased (12%) and the mean C max and AUC were slightly decreased (8% and 9%, respectively).
Distribution: After intravenous dosing in normal subjects, the volume of distribution was 8.8 L (113 mL/kg), and the total body clearance was 47.8 mL/min. Protein binding was greater than 99.5%.
Metabolism: Glimepiride is completely metabolized by oxidative biotransformation after either an intravenous or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 II C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about 1/3 of the pharmacological activity as compared to the parent compound in an animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear.
Elimination: When 14 C-glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that 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 has been observed.
Elderly: There is no significant difference in glimepiride pharmacokinetics between the elderly and younger subjects. The mean AUC at steady state for the older patients is about 13% lower than that for the younger patients; the mean weight-adjusted clearance for the older patients was about 11% higher than that for the younger patients
Patients with renal impairment: Glimepiride serum levels decreases as renal function decreases. However, M1 and M2 serum levels (mean AUC values) increased with decrease in renal function. The apparent terminal half-life (t 1/2) for glimepiride does not change, while the half-lives for M1 and M2 increased as renal function decreased.
Patients with hepatic impairment: No studies have been performed in patients with hepatic insufficiency.
Pioglitazone HCl
Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.
Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (> 99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (> 98%) to serum albumin.
Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. Urinary 6(beta)-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.
Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces. The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr.
Elderly: 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.
Patients with renal impairment: The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects.
Patients with hepatic impairment: 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.
Metformin HCl
Absorption: After an oral dose of metformin, Tmax is reached in 2.5 hours. Absolute bioavailability of a 500 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in feces was 20-30%. After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 1 µg/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 µg/ml even at maximum doses. Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min prolongation of time to peak plasma concentration was observed. The clinical relevance of this decrease is unknown.
Distribution: Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean Vd ranged between 63 – 276 l.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of metformin is >400ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
Elderly: 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 C max 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.
Patients with renal impairment: In patients with decreased renal function (based on creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
Patients with hepatic impairment: No pharmacokinetic studies of metformin have been conducted in subjects with hepatic insufficiency.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Congestive Heart Failure and other cardiac effects: Thiazolidinediones, including pioglitazone, which is a component of the fixed dose combination, can cause fluid retention in some patients when used alone or in combination with other anti-diabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure.
After initiation of the fixed dose combination, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). Heart failure should be managed according to the current standards of care. Furthermore, discontinuation or dose reduction of the fixed dose combination must be considered. The fixed dose combination is not recommended in patients with symptomatic heart failure
Lactic acidosis : Lactic acidosis is a rare, but serious, metabolic complication that can occur due to accumulation of metformin when used alone or in combination with other anti-hyperglycemic agents; when it occurs, it is fatal in approximately 50% of cases. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 µg/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). 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 onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. 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.
Hepatic Effects: In pre-approval clinical studies worldwide, over 4,500 subjects were treated with pioglitazone. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. However, in post-marketing experience with pioglitazone, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pending the availability of the results of additional large, long-term controlled clinical trials and additional post-marketing safety data on pioglitazone, it is recommended that patients treated with the fixed dose combination undergo periodic monitoring of liver enzymes. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with the fixed dose combination should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2.5 times the upper limit of normal) at baseline or any time during therapy with the fixed dose combination should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with the fixed dose combination in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the upper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient has jaundice, the fixed dose combination therapy should be discontinued.
Monitoring of renal function: Metformin is known to be substantially excreted by the kidney and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive the fixed dose combination. Before initiation of therapy with the fixed dose combination and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and the fixed dose combination discontinued if evidence of renal impairment is present.
Do not use Pioglitazone in patients with active bladder cancer. Use Pioglitazone with caution in patients with prior history of bladder cancer. The benefits of blood sugar control with Pioglitazone should be weighed against the unknown risk of cancer recurrence.
Use of intravascular iodinated contrast materials: Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, the fixed dose combination should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
Hypoxic States: Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients receiving the fixed dose combination therapy, the drug should be promptly discontinued.
Macular Edema: 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 some patients appear to have been diagnosed on routine ophthalmologic examination. Some patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. It is unknown whether or not there is a causal relationship between pioglitazone and macular edema. Patients with diabetes should have regular eye exams by an ophthalmologist. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient`s underlying medications or other physical findings.
Fractures: The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.
Hypoglycaemia: Hypoglycaemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with hypoglycemic agents (such as sulphonylureas or insulin) or ethanol. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycaemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs.
Patients receiving pioglitazone in combination with insulin or oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary
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 metformin.
Loss of control of blood glucose: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold the diabetic regime and temporarily administer insulin. The oral anti-diabetic therapy may be reinstituted after the acute episode is resolved.
Surgical procedure: Oral anti-diabetic therapy should be temporarily 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.
Type 1 diabetes: Pioglitazone and metformin exert their anti-hyperglycemic effect only in the presence of insulin. Therefore, the fixed dose combination should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Edema: In clinical studies, the incidence of edema has been reported more frequently in patients treated with pioglitazone than in placebo-treated patients and appears to be dose related.
Weight Gain: Dose related weight gain was observed with pioglitazone alone and in combination with other hypoglycemic agents. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.
Ovulation: Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. Thus, adequate contraception in premenopausal women should be recommended while taking the fixed dose combination. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known.
Hematologic: Across all clinical studies with pioglitazone, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects. the fixed dose combination may cause decreases in hemoglobin and hematocrit.
Renal impairment: Since metformin is contraindicated in patients with renal impairment; the fixed dose combination is also contraindicated in these patients.
Hepatic impairment: Therapy with the fixed dose combination should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceeds 2.5 times the upper limit of normal.
Bladder cancer: Do not use Pioglitazone in patients with active bladder cancer. Use Pioglitazone with caution in patients with prior history of bladder cancer. The benefits of blood sugar control with Pioglitazone should be weighed against the unknown risk of cancer recurrence.
DRUG INTERACTIONS
Cationic drugs: Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretions (e.g.: amiloride, cimetidine, digoxin, morphine, procainamide, quinidine, ranitidine, or vancomycin) may decrease metformin elimination by competing for common renal tubular transport systems. Hence, careful patient monitoring and dose adjustment of metformin and/or interfering cationic drug is recommended.
Miconazole (systemic route, oromucosal gel) and Phenylbutazone (systemic route): Increases hypoglycemic effect of glimepiride.
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 C max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C max 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.
Vitamin B 12: Metformin may result in suboptimal oral vitamin B 12 absorption by competitively blocking the calcium dependent binding of the intrinsic factor vitamin B 12 complex to its receptor. The reaction very rarely results in pernicious anemia that is reversible with discontinuation of metformin or with vitamin B 12 supplementation.
Nifedepine: Nifedepine appears to enhance the absorption of metformin, it increases plasma metformin C max and AUC by 20% and 9% respectively and increases the amount of metformin excreted in the urine. Metformin has minimal effects on nifedipine.
Danazol: If the use of this active substance cannot be avoided, warn the patients and emphasize the importance of urine and blood glucose monitoring. It may be necessary to adjust the dose of glimepiride, pioglitazone and metformin during and after treatment with danazol.
Salicylates: If salicylates are administered or discontinued in patients receiving oral anti-diabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control.
Thiazide: Interactions between thiazide diuretics and oral antidiabetic agents decreases insulin sensitivity thereby leading to glucose intolerance and hyperglycaemia, thus leading to a loss of diabetic control. Hence diabetic patients should be monitored closely.
CYP2C8 inhibitors/ inducers: An enzyme inhibitor of CYP2C8 (such as gemfibrozil) may significantly increase the AUC of pioglitazone and an enzyme inducer of CYP2C8 (such as rifampin) may significantly decrease the AUC of pioglitazone. Therefore, if an inhibitor or inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response.
Oral Contraceptives: Administration of pioglitazone with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both hormones by approximately 30%, which could result in loss of contraception. The pharmacokinetics of co-administration of pioglitazone and oral contraceptives has not been evaluated in patients receiving pioglitazone and an oral contraceptive. Also, oral contraceptives can cause hyperglycemia and lead to loss of glycemic control. Therefore, additional caution regarding contraception should be exercised in patients receiving pioglitazone and an oral contraceptive.
Other: Concomitant administration of angiotensin enzyme inhibitors (captopril, enalapril), other antidiabetic drugs (insulin, acarbose) beta-blockers, fluconozole, histamine (H2) receptor antagonist, monoamine oxidase inhibitors (MAOIs), sulphonamides and non-steroidal anti-inflammatory agents increases sensitivity to insulin and potentiation of blood glucose lowering effect and thus ,in some instances, hypoglycemia may occur . Dosage of the fixed dose combination may need to be reduced. Patients receiving corticosteroids, phenothiazines, thyroid products, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and isoniazid should be closely monitored for loss of diabetic control when therapy is instituted or discontinued. When such drugs are administered to a patient receiving the fixed dose combination, the patient should be closely observed to maintain adequate glycemic control.
ADVERSE EFFECTS
Clinical trials using triple drug treatment to attain HbA1c levels of less than 7% have shown that there is an increased risk of developing symptomatic hypoglycemia. The risk of severe hypoglycemia however is not substantially elevated.
Glimepiride: Glimepiride appears to be associated with a low incidence of hypoglycemia.
Pioglitazone HCl: Adverse events such as edema, headache, upper respiratory tract infection, myalgia, sinusitis, and pharyngitis have been reported with pioglitazone therapy. Cases of anemia have been reported infrequently in patients treated with pioglitazone
Metformin HCl: Nausea, diarrhea, gastric pain, constipation, vomiting, metallic taste in mouth have been reported with metformin therapy. These reactions are generally dose related and disappear when the dose is reduced
USE IN PREGNANCY AND LACTATION
Since recent information has suggested that abnormal blood glucose levels during pregnancy are associated with higher incidence of congenital abnormalities, most experts suggest insulin be used to maintain the blood glucose levels as close to normal as possible. The use of the fixed dose combination is not recommended for use in pregnancy. Studies in lactating rats have shown that metformin and pioglitazone is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted on nursing mothers. Glimepiride should not be used by breast-feeding mothers. Hence, the use of the fixed dose combination is contraindicated in lactating mothers, and if the diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
OVERDOSAGE
Glimepiride: Overdosage of sulphonylureas, including glimepiride, can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger.
Severe hypoglycemic reactions, with coma, convulsions or other neurological disorders are possible and must be treated as medical emergency, requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid I.V. injection of 50 ml of concentrated glucose solution (20 to 30 %). This must be followed by the infusion of more dilute glucose solution (10 %) at a rate that will maintain blood glucose levels above 1g/L. Patients should be monitored closely and, depending on the patients’ condition after this time, the doctor will decide if further monitoring is necessary. Dialysis is not beneficial to patient due to strong binding of glimepiride to plasma proteins
Pioglitazone HCl: 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 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 HCl: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. 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 overdose cases. 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 drug from patients in whom metformin overdosage is suspected.
CAUTION:
Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.
STORE AT TEMPERATURES NOT EXCEEDING 300C
AVAILABILITY
Pioglitazone HCl + Metformin HCl + Glimepiride (Tri-Senza®) 15mg/500mg/1mg Tablet X 30 tablets / box in alu-alu blister pack
Pioglitazone HCl + Metformin HCl + Glimepiride (Tri-Senza®) 15mg/850mg/1mg Tablet X 30 tablets / box in alu-alu blister pack
Pioglitazone HCl + Metformin HCl + Glimepiride (Tri-Senza®) 15mg/500mg/2mg Tablet X 30 tablets / box in alu-alu blister pack
Pioglitazone HCl + Metformin HCl + Glimepiride (Tri-Senza®) 15mg/850mg/2mg Tablet X 30 tablets / box in alu-alu blister pack
