General Precautions: Pioglitazone HCl:
Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore, Actosmet should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
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.
In U.S. placebo-controlled clinical trials that excluded patients with 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 versus 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 (see Pioglitazone HCl under Warnings). 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 post-marketing experience with pioglitazone, cases of congestive heart failure have been reported in patients both with and without previously known heart disease.
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 (see Adverse Reactions). In post-marketing 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, Actosmet should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure (see Congestive Heart Failure under Warnings and Information for Patients as follows).
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. (See Table 3.)
Click on icon to see table/diagram/image
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 Actosmet. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known.
Across all clinical studies with pioglitazone, mean hemoglobin values declined by 2-4% in patients treated with pioglitazone. These changes primarily occurred within the first 4-12 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 (see Laboratory Abnormalities under Adverse Reactions). Actosmet may cause decreases in hemoglobin and hematocrit.
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 post-marketing experience with pioglitazone, reports of hepatitis and of hepatic enzyme elevations to ≥3 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 Actosmet undergo periodic monitoring of liver enzymes.
Serum alanine aminotransferase (ALT) levels should be evaluated prior to the initiation of therapy with Actosmet in all patients and periodically thereafter, per clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur eg, nausea, vomiting, abdominal pain, fatigue, anorexia or dark urine. The decision whether to continue the patient on therapy with Actosmet should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.
Therapy with Actosmet 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 1-2.5 times the upper limit of normal) at baseline or any time during therapy with Actosmet should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with Actosmet 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 pre-treatment 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, Actosmet therapy should be discontinued.
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 (see Adverse Reactions).
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 1st 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 standard of care.
General Precautions: Metformin HCl: 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 Actosmet. In patients with advanced age, Actosmet 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, renal function should be monitored regularly and generally, Actosmet should not be titrated to the maximum dose of the metformin component (see Dosage & Administration and Metformin HCl under Warnings).
Before initiation of therapy with Actosmet 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 Actosmet 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 eg, cationic drugs that are eliminated by renal tubular secretion (see Precautions and Interactions), should be used with caution.
Radiologic Studies Involving the Use of Intravascular Iodinated Contrast Materials (for example, IV urogram, IV 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 (see Contraindications). Therefore, in patients in whom any such study is planned, Actosmet should be temporarily discontinued at the time of or prior to the procedure and withheld for 48 hrs subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
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 Actosmet therapy, the drug should be promptly discontinued.
Use of Actosmet 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 is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Actosmet.
Impaired Hepatic Function:
Since impaired hepatic function has been associated with some cases of lactic acidosis, Actosmet should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 Levels:
In controlled clinical trials of metformin at 29-weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Actosmet and any apparent abnormalities should be appropriately investigated and managed (see General Precautions: Metformin HCl as previously-mentioned and Laboratory Tests). 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 2- to 3-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 Actosmet who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate and metformin levels. If acidosis of either form occurs, Actosmet must be stopped immediately and other appropriate corrective measures initiated (see Metformin HCl under Warnings).
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 (eg, 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 β-adrenergic blocking drugs.
Loss of Control of Blood Glucose:
When a patient stabilized on any diabetic regimen is exposed to stress eg, fever, trauma, infection or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Actosmet and temporarily administer insulin. Actosmet may be reinstituted after the acute episode is resolved.
FPG and A1C measurements should be performed periodically to monitor glycemic control and therapeutic response to Actosmet.
Liver enzyme monitoring is recommended prior to initiation of therapy with Actosmet in all patients and periodically thereafter, per the clinical judgment of the health care professional (see General Precautions: Pioglitazone HCl as previously-mentioned and Serum Transaminase Levels under Adverse Reactions).
Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, vitamin B12 deficiency should be excluded.
Information for Patients: Patients should be instructed regarding the importance of adhering to dietary instructions, a regular exercise program and regular testing of blood glucose and A1C. During periods of stress eg, fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly.
The risks of lactic acidosis, its symptoms and conditions that predispose to its development, as noted in Warnings and General Precautions: Metformin HCl as previously cited, should be explained to patients. Patients should be advised to discontinue Actosmet immediately and to promptly notify their health care professional if unexplained hyperventilation, myalgia, malaise, unusual somnolence or other nonspecific symptoms occur. Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of Actosmet therapy; however, patients should consult with their physician if they develop unexplained symptoms. Although gastrointestinal symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious disease.
Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving Actosmet.
Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on Actosmet should immediately report these symptoms to their physician.
Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter, per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia or dark urine.
Patients should be informed about the importance of regular testing of renal function and hematologic parameters when receiving treatment with Actosmet.
Therapy with a thiazolidinedione, which is the active pioglitazone component of the Actosmet tablet, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Actosmet. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known.
Combination antihyperglycemic therapy may cause hypoglycemia. When initiating Actosmet, the risks of hypoglycemia, its symptoms and treatment and conditions that predispose to its development should be explained to patients.
Patients should be told to take Actosmet as prescribed and instructed that any change in dosing should only be done if directed by their physician.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Actosmet:
No animal studies have been conducted with Actosmet. The following data are based on findings in studies performed with pioglitazone or metformin individually.
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 2-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 >1800 patients receiving pioglitazone in clinical trials up to 1 year in duration, no new cases of bladder tumors were identified. In two 3-year studies in which pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was <1 year at the time of diagnosis of bladder cancer, there were 6 (0.16%) cases on pioglitazone and 2 (0.05%) on placebo.
Pioglitazone 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
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
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 4 times a human daily dose of 2000 mg of the metformin component of Actosmet based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with 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 3 times the maximum recommended human daily dose of the metformin component of Actosmet based on body surface area comparisons.
Use in pregnancy: Actosmet:
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. Actosmet 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 Actosmet or its individual components. No animal studies have been conducted with the combined products in Actosmet. The following data are based on findings in studies performed with pioglitazone or metformin individually.
Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m2
, respectively). Delayed parturition and embryotoxicity (as evidenced by increased post-implantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of ≥40 mg/kg/day (approximately 10 times the maximum recommended human oral dose based on mg/m2
). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m2
). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of ≥10 mg/kg during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m2
Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times a human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Use in lactation:
No studies have been conducted with the combined components of Actosmet. In studies performed with the individual components, both pioglitazone and metformin are secreted in the milk of lactating rats. It is not known whether pioglitazone and/or metformin is secreted in human milk. Because many drugs are excreted in human milk, Actosmet should not be administered to a breastfeeding woman. If Actosmet is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Use in children:
Safety and effectiveness of Actosmet in pediatric patients have not been established.
Use in the elderly: Pioglitazone HCl:
Approximately 500 patients in placebo-controlled clinical trials of pioglitazone were ≥65 years. No significant differences in effectiveness and safety were observed between these patients and younger patients.
Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Actosmet should only be used in patients with normal renal function (see Special Populations under Pharmacokinetics under Actions, Contraindications, Metformin HCl under Warnings). Because aging is associated with reduced renal function, Actosmet should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Actosmet (see Dosage & Administration and Metformin HCl under Warnings).