I am diabetic

Possible side effects
Get emergency medical help if you have any of these symptoms of lactic acidosis:

• weakness,
• increasing sleepiness,
• slow heart rate,
• cold feeling,
• muscle pain,
• shortness of breath,
• stomach pain,
• feeling light-headed,
• and fainting.

Stop using metformin and pioglitazone and get emergency medical help if you have any of these signs of an allergic reaction:

• hives;
• difficulty breathing;
• swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

• feeling short of breath, even with mild exertion;
• swelling or rapid weight gain; or
• nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Other less serious side effects may be more likely to occur, such as:

• sneezing, runny nose, cough or other signs of a cold;
• dizziness;
• headache;
• mild nausea, vomiting, diarrhea, stomach pain; or
• joint or muscle pain.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

 

What other drugs will affect ActoPlus Met?
You may be more likely to have hyperglycemia (high blood sugar) if you are taking metformin and pioglitazone with other drugs that raise blood sugar. Drugs that can raise blood sugar include:

• isoniazid;
• diuretics (water pills);
• steroids (prednisone and others);
• phenothiazines (Compazine and others);
• thyroid medicine (Synthroid and others);
• birth control pills and other hormones;
• seizure medicines (Dilantin and others); and
• diet pills or medicines to treat asthma, colds or allergies.

You may be more likely to have hypoglycemia (low blood sugar) if you are taking metformin and pioglitazone with other drugs that lower blood sugar. Drugs that can lower blood sugar include:

• nonsteroidal anti-inflammatory drugs (NSAIDs);
• aspirin or other salicylates (including Pepto-Bismol);
• sulfa drugs (Bactrim and others);
• a monoamine oxidase inhibitor (MAOI);
• beta-blockers (Tenormin and others); or
• probenecid (Benemid).

Some medications may interact with metformin and pioglitazone. Tell your doctor if you are using any of the following drugs:

• furosemide (Lasix);
• nifedipine (Adalat, Procardia);
• cimetidine (Tagamet) or ranitidine (Zantac);
• amiloride (Midamor) or triamterene (Dyrenium);
• digoxin (Lanoxin);
• morphine (MS Contin, Kadian, Oramorph);
• procainamide (Procan, Pronestyl, Procanbid);
• quinidine (Cardioquin, Quinidex, Quinaglute);
• trimethoprim (Proloprim, Primsol, Bactrim, Cotrim, Septra); or
• vancomycin (Vancocin, Lyphocin).

If you are using any of these drugs, you may not be able to take metformin and pioglitazone, or you may require a dosage adjustment or special monitoring.
There may be other drugs not listed that can affect metformin and pioglitazone. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

 

What should I avoid while taking ActoPlus Met?
Some conditions may increase the risk of developing lactic acidosis while taking metformin and pioglitazone. Tell your doctor that you are taking metformin and pioglitazone if you become ill; if you have a heart attack; have a stroke; develop congestive heart failure; experience diarrhea, vomiting, fever, or dehydration from any cause; decrease the amount of food or liquid in your normal diet, or develop other health conditions. You may need to stop treatment with metformin and pioglitazone for a short amount of time until you are feeling better.
Avoid excessive alcohol intake while taking metformin and pioglitazone. Together, alcohol and metformin and pioglitazone may increase the risk of lactic acidosis and hypoglycemia. Follow diet, medication, and exercise routines very closely. Changing any of these things can affect blood sugar levels.
Tell your doctor or other health care provider that you are taking this medication if you need to have surgery or x-ray procedures that require injection of contrast agents. Treatment with metformin and pioglitazone may need to be stopped for a short period of time.

Contraindications
Initiation of Actoplus Met in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.
In addition, Actoplus Met is contraindicated in patients with:

• Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ? 1.5 mg/dL [males], ? 1.4 mg/dL [females], or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
• 2. Known hypersensitivity to pioglitazone, metformin or any other component of Actoplus Met.
• 3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Actoplus Met should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

 

Warnings
Metformin hydrochloride
Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Actoplus Met (pioglitazone hydrochloride and metformin hydrochloride) tablets; when it occurs, it is fatal 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 �g/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 more than 20,000 patient-years exposure to 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 of age 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.
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. 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. 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 less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.
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.

Pioglitazone hydrochloride
Cardiac Failure and Other Cardiac Effects: Pioglitazone, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antihyperglycemic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone must be considered. Patients with NYHA Class III and IV cardiac status were not studied during pre-approval clinical trials and pioglitazone is not recommended in these patients.

Precautions

Pioglitazone hydrochloride
Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore, Actoplus Met should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hypoglycemia
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.

Cardiovascular
In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with pioglitazone as monotherapy or in combination with sulfonylureas or metformin vs. placebo-treated patients. In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with pioglitazone in combination with insulin. Patients with NYHA Class III and IV cardiac status were not studied in pre-approval pioglitazone clinical trials. Pioglitazone is not indicated in patients with NYHA Class III or IV cardiac status.
In postmarketing experience with pioglitazone, cases of congestive heart failure have been reported in patients both with and without previously known heart disease.

Edema
In all U.S. clinical trials with pioglitazone, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and appears to be dose related. In postmarketing experience, reports of initiation or worsening of edema have been received. Since thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Actoplus Met should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure.

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 Actoplus Met. 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. Actoplus Met may cause decreases in hemoglobin and hematocrit.

Hepatic Effects
In pre-approval clinical studies worldwide, over 4500 subjects were treated with pioglitazone. In U.S. clinical studies, over 4700 patients with type 2 diabetes received pioglitazone. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies.
During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with pioglitazone and 2 of 793 (0.25%) placebo-treated patients had ALT values ? 3 times the upper limit of normal. The ALT elevations in patients treated with pioglitazone were reversible and were not clearly related to therapy with pioglitazone.
In postmarketing 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 postmarketing safety data on pioglitazone, it is recommended that patients treated with Actoplus Met undergo periodic monitoring of liver enzymes.
Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with Actoplus Met in all patients and periodically thereafter per the clinical judgment of the health care professional. 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 Actoplus Met should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.
Therapy with Actoplus Met should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. 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 Actoplus Met should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with Actoplus Met 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 is jaundiced, Actoplus Met therapy should be 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, per the Standards of Care of the American Diabetes Association. 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
In a randomized trial (PROactive) in patients with type 2 diabetes (mean duration of diabetes 9.5 years), an increased incidence of bone fracture was noted in female patients taking pioglitazone. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and remained during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in fracture rates was observed in men treated with pioglitazone 1.7% (30/1735) versus placebo 2.1% (37/1728). 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.

Metformin hydrochloride
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 Actoplus Met. In patients with advanced age, Actoplus Met should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ? 80 years of age, renal function should be monitored regularly and, generally, Actoplus Met should not be titrated to the maximum dose of the metformin component.
Before initiation of therapy with Actoplus Met 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 Actoplus Met discontinued if evidence of renal impairment is present.
Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution.
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): Intravascular contrast studies with iodinated 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, Actoplus Met 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 Actoplus Met therapy, the drug should be promptly discontinued.

Surgical procedures
Use of Actoplus Met 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.

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 Actoplus Met.

Impaired hepatic function
Since impaired hepatic function has been associated with some cases of lactic acidosis, Actoplus Met 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 is advised in patients on Actoplus Met and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at two- to three-year intervals may be useful.

Change in clinical status of patients with previously controlled type 2 diabetes
A patient with type 2 diabetes previously well-controlled on Actoplus Met 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 include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate and metformin levels. If acidosis of either form occurs, Actoplus Met must be stopped immediately and other appropriate corrective measures initiated.

Hypoglycemia
Hypoglycemia 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 sulfonylureas 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. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs.

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 Actoplus Met and temporarily administer insulin. Actoplus Met may be reinstituted after the acute episode is resolved.

Information For Patients

Carcinogenesis/ Mutagenesis/ Impairment of Fertility
No animal studies have been conducted with Actoplus Met. The following data are based on findings in studies performed with pioglitazone or metformin individually.

Pioglitazone hydrochloride
A two-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/day and above (approximately equal to the maximum recommended human oral dose based on mg/m2). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (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 more than 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 less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) on placebo.
Pioglitazone HCl 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 40 mg/kg pioglitazone HCl 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/day and 1500 mg/kg/day, respectively. These doses are both approximately four times a human daily dose of 2000 mg of the metformin component of Actoplus Met 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 metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
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/day, which is approximately three times the maximum recommended human daily dose of the metformin component of Actoplus Met based on body surface area comparisons.

Pregnancy
Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Actoplus Met should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.
There are no adequate and well-controlled studies in pregnant women with Actoplus Met or its individual components. No animal studies have been conducted with the combined products in Actoplus Met. The following data are based on findings in studies performed with pioglitazone or metformin individually.

Nursing Mothers
No studies have been conducted with the combined components of Actoplus Met. 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, Actoplus Met should not be administered to a breastfeeding woman. If Actoplus Met is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use
Safety and effectiveness of Actoplus Met in pediatric patients have not been established.

Geriatric Use
Pioglitazone hydrochloride
Approximately 500 patients in placebo-controlled clinical trials of pioglitazone were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients.

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, Actoplus Met should only be used in patients with normal renal function. Because aging is associated with reduced renal function, Actoplus Met 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 Actoplus Met.

Product Description

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Pharmacokinetics

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Absorption
In bioequivalence studies of Actoplus Met 15 mg/500 mg and 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 Glucophage� (500 mg or 850 mg, respectively) tablets under fasted conditions in healthy subjects.
Administration of Actoplus Met 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 hours for pioglitazone and 0.8 hours 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 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.

Metformin hydrochloride
The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximately 50% – 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 minute 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 hours and are generally <1 �g/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 �g/mL, even at maximum doses.

Metabolism
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% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC.
In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 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. Urinary 6?-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.

Metformin hydrochloride
Intravenous 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 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 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Excretion
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.

Special Populations

Geriatric
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.
Actoplus Met treatment should not be initiated in patients ? 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.

Pediatric
Pioglitazone hydrochloride
Pharmacokinetic data in the pediatric population are not available.

Metformin hydrochloride
After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), 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 Cmax and AUC values were increased 20% to 60% in females. In controlled clinical trials, hemoglobin A1C(A1C) decreases from baseline were generally greater for females than for males (average mean difference in A1C 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.

Race
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).

Renal Insufficiency
Pioglitazone hydrochloride
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.

Metformin hydrochloride
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. Since metformin is contraindicated in patients with renal impairment, Actoplus Met is also contraindicated in these patients.

Hepatic Impairment
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 Actoplus Met 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.

Metformin hydrochloride
No pharmacokinetic studies of metformin have been conducted in subjects with hepatic insufficiency.

Product Description

Most important information about Actos

Side Effects

More information about ACTOPLUS MET (Pioglitazone/Metformin):

Laboratory Abnormalities

FDA MedWatch Alerts

ACTOplus met Approved by the FDA for Type 2 Diabetes

To buy ACTOPLUS MET click HERE: My Family Drugstore

What is the most important information I should know about ActoPlus Met?
Lactic acidosis, which can be fatal, may occur while taking ActoPlus Met.
Symptoms include:

• general body discomfort,
• muscle pain,
• breathing problems,
• increasing drowsiness,
• upset stomach,
• cold skin,
• dizziness,
• tiredness,
• lightheadedness,
• and slowed heartbeat.

If any of these symptoms occur, seek medical attention at once.
Lactic acidosis is more likely to occur in patients who have heart failure, kidney or liver problems, a lack of body fluids or dehydration, x-ray or scanning procedures that require an injectable iodinated contrast drug, surgery, serious infection, heart attack, stroke, or who use alcohol excessively. Also at higher risk are the elderly, especially those older than 80 years of age who have not had kidney and liver function tests.
Thiazolidinedione antidiabetics such as ActoPlus Met may cause or worsen heart failure in some patients. Tell your doctor if you have a history of heart failure. ActoPlus Met should not be used to treat patients with moderate to severe heart failure. You will be monitored for signs of heart failure when you start ActoPlus Met and when your dose increases. Contact your doctor at once if you develop swelling of the hands, ankles, or feet; shortness of breath; or sudden unexplained weight gain. Your doctor may need to stop your medicine or change your dose.
Avoid excessive alcohol intake while taking metformin and pioglitazone. Together, alcohol and metformin and pioglitazone may increase the risk of lactic acidosis and hypoglycemia.
Metformin and pioglitazone does not usually cause hypoglycemia (low blood sugar). Nevertheless, hypoglycemia may occur, as a result of skipped meals, excessive exercise, or alcohol consumption. Know the signs and symptoms of low blood sugar, which include:

• hunger,
• headache,
• drowsiness,
• weakness,
• dizziness,
• a fast heartbeat,
• sweating,
• tremor,
• and nausea.

Carry a non-dietetic candy or glucose tablets to treat episodes of low blood sugar.

What should I discuss with my doctor before taking ActoPlus Met?
Do not take metformin and pioglitazone without first talking to your doctor if you:

• have type 1 diabetes;
• have liver or kidney disease;
• have acute or chronic metabolic acidosis, including diabetic ketoacidosis;
• have congestive heart failure;
• have had a heart attack or a stroke;
• have a serious infection, illness, or injury;
• need to have surgery;
• need to have x-rays or other procedures using injectable contrast agents;
• are dehydrated (have lost water from your body) due to diarrhea, vomiting, fever, heat stroke, decreased fluid intake, or any other cause;
• have edema (water retention or swelling);
• drink alcohol; or
• are 80 years of age or older and have not had your kidney function tested.

You may not be able to take metformin and pioglitazone, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.
Treatment with metformin and pioglitazone may cause resumption of fertility by allowing the return of ovulation (production of eggs) in certain women with insulin resistance who were not ovulating before treatment with metformin and pioglitazone. Talk to your doctor about adequate forms of birth control while taking metformin and pioglitazone if birth control is desired.
Contact your doctor if you develop a fever or an infection, require surgery, or if you experience a serious injury. Illness or injury may cause a loss of blood sugar control and insulin (or an adjustment of a current insulin dose) may be required for a period of time.
Metformin and pioglitazone is in the FDA pregnancy category C. This means that it is not known whether it will be harmful to an unborn baby. Generally, insulin is the drug of choice for controlling diabetes during pregnancy. Do not take metformin and pioglitazone without first talking to your doctor if you are pregnant or could become pregnant during treatment.
It is not known whether metformin and pioglitazone passes into breast milk. Do not take metformin and pioglitazone without first talking to your doctor if you are breast-feeding a baby.
If you are over the age of 65 years, there may be an slight increase in the risk of developing lactic acidosis due to a natural decline in kidney function with advancing age. A lower dose or special monitoring may be necessary during treatment.

Product Description

Pharmacokinetics

Side Effects

More information about ACTOPLUS MET (Pioglitazone/Metformin):

Laboratory Abnormalities

FDA MedWatch Alerts

ACTOplus met Approved by the FDA for Type 2 Diabetes

To buy ACTOPLUS MET click HERE: My Family Drugstore

Drug Name
Actoplus Met (Pioglitazone/Metformin)

Generic Name
Pioglitazone hydrochloride and Metformin hydrochloride (Pye-oh-GLI-ta-zone/ MET-fore-min)

Manufacturer / Distributor
Takeda

Looks like
Metformin and pioglitazone is available with a prescription under the brand name Actoplus Met. Other brand or generic formulations may also be available. Ask your pharmacist any questions you have about this medication, especially if it is new to you.

• Actoplus Met 15 mg/500 mg (pioglitazone/metformin)-off white oval, film-coated tablets
• Actoplus Met 15 mg/850 mg (pioglitazone/metformin)-off white pink, oval, film-coated tablets

Dosage Form
Tablets

Route Of Administration
ORAL

Imprint Code
4833M;15/500 / 4833M;15/850

Size
14mm / 18mm

Alternatives
Actos, Avandia, Avandamet

Drug Uses
Actoplus Met is a combination of two oral diabetes medicines (Metformin and Pioglitazone) that help control blood sugar levels with diet and exercise, in patients with type 2 diabetes who are already being treated with both of these medications, who are not adequately controlled on metformin alone, or who have responded to pioglitazone alone but require additional control.
ActoPlus Met is a combination of an insulin resistance reducer and a biguanide. This combination medicine works in 2 ways to improve blood glucose levels (sugar). Pioglitazone helps the cells use glucose, and metformin slows the liver’s production of glucose. Controlling high blood sugar helps prevent heart disease, strokes, kidney disease, blindness, circulation problems, and sexual function problems (impotence).

Drug class
Actoplus Met is a combination of an insulin resistance reducer and a biguanide, used along with a diet and exercise program to control high blood sugar in certain diabetic patients.

Contains
Actoplus Met� (pioglitazone hydrochloride and metformin hydrochloride) tablets contain two 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.

Inactive ingredients:

• povidone
• microcrystalline cellulose
• croscarmellose sodium
• magnesium stearate
• hypromellose 2910
• polyethylene glycol 8000
• titanium dioxide
• talc

Chemical formula
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 ?-glucosidase inhibitors. The molecule contains one asymmetric center, and the synthetic compound is a racemate. The two enantiomers of pioglitazone interconvert in vivo. The structural formula is as shown:

Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of C19H20N2O3S�HCl and a molecular weight of 392.90. 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 a 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. The structural formula is as shown:

Actoplus Met is available as a tablet for oral administration containing 15 mg pioglitazone hydrochloride (as the base) with 500 mg metformin hydrochloride (15 mg/500 mg) or 15 mg pioglitazone hydrochloride (as the base) with 850 mg metformin hydrochloride (15 mg/850 mg) formulated with the following excipients: povidone USP, microcrystalline cellulose NF, croscarmellose sodium NF, magnesium stearate NF, hypromellose 2910 USP, polyethylene glycol 8000 NF, titanium dioxide USP, and talc USP.

Mechanism of Action
Actoplus Met combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with 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 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. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPAR?). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR? 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.
Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

Metformin hydrochloride
Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases 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) 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.

How Taken
Take metformin and pioglitazone exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain the instructions to you.
Take each dose with a full glass of water.
Take metformin and pioglitazone with meals to reduce nausea, diarrhea, and upset stomach that may occur with metformin and pioglitazone therapy. These symptoms may be more likely to occur during the first few weeks of therapy.
It is important to take metformin and pioglitazone regularly to get the most benefit.
A decrease in vitamin B12 may also occur during metformin and pioglitazone therapy. Your doctor may want to monitor blood levels of vitamin B12 and you may need to take a B12 supplement. A vitamin B12 deficiency may rarely cause anemia.
Your medication needs may change if you become sick or injured, if you have a serious infection, or if you have any type of surgery. Your doctor may want you to stop taking metformin and pioglitazone for a short time if any of these situations affect you.
Take care not to let your blood sugar get too low, causing hypoglycemia. You may have hypoglycemia if you skip a meal, exercise too long, drink alcohol, or are under stress.
Know the signs of low blood sugar (hypoglycemia) and how to recognize them:

• hunger, headache, confusion, irritability;
• drowsiness, weakness, dizziness, tremors;
• sweating, fast heartbeat;
• seizure (convulsions); or
• fainting, coma (severe hypoglycemia can be fatal).

Always keep a source of sugar available in case you have symptoms of low blood sugar. Sugar sources include orange juice, glucose gel, candy, or milk. If you have severe hypoglycemia and cannot eat or drink, use an injection of glucagon. Your doctor can give you a prescription for a glucagon emergency injection kit and tell you how to give the injection.
Usually, liver function is monitored with blood tests at the start of treatment, every two months for the first year of treatment, and periodically thereafter during treatment with pioglitazone. Notify your doctor immediately if you develop nausea, vomiting, abdominal pain, unusual fatigue, loss of appetite, yellow skin or eyes, or dark urine. These symptoms may be early signs of liver problems.

Dosage and Administration
The use of antihyperglycemic therapy in the management of type 2 diabetes should be individualized on the basis of effectiveness and tolerability while not exceeding the maximum recommended daily dose of pioglitazone 45 mg and metformin 2550 mg.

Usual Starting Dose
Selecting the starting dose of Actoplus Met should be based on the patient’s current regimen of pioglitazone and/or metformin. After initiation of Actoplus Met or with dose increase, patients should be carefully monitored for adverse events related to fluid retention. Actoplus Met should be given in divided daily doses with meals to reduce the gastrointestinal side effects associated with metformin.
Starting dose for patients inadequately controlled on metformin monotherapy
Based on the usual starting dose of pioglitazone (15-30 mg daily), Actoplus Met may be initiated at either the 15 mg/500 mg or 15 mg/850 mg tablet strength once or twice daily, and gradually titrated after assessing adequacy of therapeutic response.
Starting dose for patients who initially responded to pioglitazone monotherapy and require additional glycemic control
Based on the usual starting doses of metformin (500 mg twice daily or 850 mg daily), Actoplus Met may be initiated at either the 15 mg/500 mg twice daily or 15 mg/850 mg tablet strength once daily, and gradually titrated after assessing adequacy of therapeutic response.
Starting dose for patients switching from combination therapy of pioglitazone plus metformin as separate tablets.

Usual Maintenance Dose
Actoplus Met may be initiated with either the 15 mg/500 mg or 15 mg/850 mg tablet strengths based on the dose of pioglitazone and metformin already being taken.
No studies have been performed specifically examining the safety and efficacy of Actoplus Met in patients previously treated with other oral hypoglycemic agents and switched to Actoplus Met. 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 A1C, which is a better indicator of long-term glycemic control than FPG alone. A1C reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with Actoplus Met for a period of time adequate to evaluate change in A1C (8-12 weeks) unless glycemic control as measured by FPG deteriorates.

Missed Dose
Take the missed dose as soon as you remember (be sure to take the medicine with food). If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time.
Do not take extra medicine to make up the missed dose.

Overdose
Seek emergency medical attention if you think you have used too much of this medicine. Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center ( http://www.aapcc.org/findyour.htm ), or emergency room immediately.
Symptoms may include:

• hunger,
• headache,
• confusion,
• irritability,
• drowsiness,
• weakness,
• dizziness,
• tremors,
• sweating,
• fast heartbeat,
• seizure (convulsions),
• fainting, or coma.

An overdose of metformin and pioglitazone may cause a life-threatening condition called lactic acidosis. Get emergency medical help if you have any of these symptoms of lactic acidosis:

• weakness,
• increasing sleepiness,
• slow heart rate,
• cold feeling,
• muscle pain,
• shortness of breath,
• stomach pain,
• feeling light-headed,
• and fainting.

Storage
Store ActoPlus Met at 77 degrees F (25 degrees C) in a tightly closed container. Store away from heat, moisture, and light. Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted.
Do not store in bathroom.
Keep ActoPlus Met out of the reach of children and away from pets.

How Supplied

Actoplus Met is available in 15 mg pioglitazone hydrochloride (as the base)/500 mg metformin hydrochloride and 15 mg pioglitazone hydrochloride (as the base)/850 mg metformin hydrochloride tablets as follows:

15 mg/500 mg tablet: white to off-white, oblong, film-coated tablet with “4833M” on one side, and “15/500″ on the other, available in:
Bottles of 60 – NDC 64764-155-60
Bottles of 180 – NDC 64764-155-18

15 mg/850 mg tablet: white to off-white, oblong, film-coated tablet with “4833M” on one side, and “15/850″ on the other, available in:
Bottles of 60 – NDC 64764-158-60
Bottles of 180 – NDC 64764-158-18

Most important information about Actos

Pharmacokinetics

Side Effects

More information about ACTOPLUS MET (Pioglitazone/Metformin):

Laboratory Abnormalities

FDA MedWatch Alerts

ACTOplus met Approved by the FDA for Type 2 Diabetes

To buy ACTOPLUS MET click HERE: My Family Drugstore