WARNINGS AND PRECAUTIONS
Congestive Heart Failure
Pioglitazone
Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with ACTOPLUS MET XR should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of ACTOPLUS MET XR must be considered [see Boxed Warning, Contraindications (4), and Adverse Reactions ].
Lactic Acidosis
Metformin hydrochloride
Lactic Acidosis
Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with ACTOPLUS MET XR and 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 concentrations (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is 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 impairment, 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, particularly when accompanied by 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. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. ACTOPLUS MET XR treatment should not be initiated in any patient unless measurement of creatinine clearance demonstrates that renal function is not reduced. 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 impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, because alcohol potentiates the effects of metformin on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids [see Warnings and Precautions (5.10, 5.11, 5.12, 5.13)]. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may frequently cause dose-dependent metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis [see Drug Interactions and Clinical Pharmacology].
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. Patients should be educated to promptly report these symptoms should they occur. If present, ACTOPLUS MET XR should be withdrawn until lactic acidosis is ruled out. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and 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 recur. 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 [see Warnings and Precautions ].
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery [see Contraindications and Warnings and Precautions].
Edema
In controlled clinical trials with pioglitazone, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose related [see Adverse Reactions ]. In postmarketing experience, reports of new onset or worsening of edema have been received. ACTOPLUS MET XR should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, ACTOPLUS MET XR should be used with caution in patients at risk for congestive heart failure. Patients treated with ACTOPLUS MET XR should be monitored for signs and symptoms of congestive heart failure [see Boxed Warning, Warnings and Precautions (5.1), and Patient Counseling Information].
Hypoglycemia
Patients receiving ACTOPLUS MET XR in combination with insulin or other anti-diabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant anti-diabetic medication may be necessary to reduce the risk of hypoglycemia [see Dosage and Administration ]. Hypoglycemia can also occur when caloric intake is deficient or when strenuous exercise is not compensated by caloric supplement. 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.
Hepatic Effects
There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date [see Adverse Reactions].
Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating ACTOPLUS MET XR therapy.
In patients with abnormal liver tests, ACTOPLUS MET XR should be initiated with caution.
Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than three times the upper limit of the reference range), ACTOPLUS MET XR treatment should be interrupted and investigation done to establish the probable cause. ACTOPLUS MET XR should not be restarted in these patients without another explanation for the liver test abnormalities.
Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury, and should not be restarted on ACTOPLUS MET XR. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with ACTOPLUS MET XR can be used with caution.
Because impaired hepatic function has been associated with some cases of lactic acidosis ACTOPLUS MET XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Urinary Bladder Tumors
Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology ]. In two 3-year trials 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%) cases on placebo.
A five-year interim report of an ongoing 10-year observational cohort study found a non-significant increase in the risk for bladder cancer in subjects ever exposed to pioglitazone, compared to subjects never exposed to pioglitazone (HR 1.2 [95% CI 0.9 − 1.5]). Compared to never exposure, a duration of pioglitazone therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9 − 2.1]), which reached statistical significance after more than 24 months of pioglitazone use (HR 1.4 [95% CI 1.03 − 2.0]). Interim results from this study suggested that taking pioglitazone longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of three cases in 10,000 (from approximately seven in 10,000 [without pioglitazone] to approximately 10 in 10,000 [with pioglitazone]).
There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, ACTOPLUS MET XR should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with ACTOPLUS MET XR should be considered in patients with a prior history of bladder cancer.
Fractures
In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force–titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. 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 persisted 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 the incidence of fracture was observed in men treated with pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with ACTOPLUS MET XR and attention should be given to assessing and maintaining bone health according to current standards of care.
Macular Edema
Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.
Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione.
Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient’s underlying medications or other physical findings [see Adverse Reactions ].
Ovulation
Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOPLUS MET XR [see Use in Specific Populations]. This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception in all premenopausal women treated with ACTOPLUS MET XR is recommended.
Monitoring of Renal Function
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Therefore, ACTOPLUS MET XR is contraindicated in patients with renal impairment.
Before initiation of therapy with ACTOPLUS MET XR and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated (e.g., elderly), renal function should be assessed more frequently and ACTOPLUS MET XR 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 [see Clinical Pharmacology ].
Radiological studies and surgical procedures
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 [see Contraindications (4)]. Therefore, in patients in whom any such study is planned, ACTOPLUS MET XR should be 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 XR therapy, the drug should be promptly discontinued.
Surgical Procedures
Use of ACTOPLUS MET XR 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 XR.
Vitamin B Levels
In controlled clinical trials of metformin of 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 XR 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.
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ACTOPLUS MET XR or any other oral anti-diabetic drug.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of ACTOPLUS MET XR or its individual components in pregnant women. Animal studies using pioglitazone show increased rates of post-implantation loss, delayed development, reduced fetal weights, and delayed parturition at doses 10 to 40 times the maximum recommended human dose. ACTOPLUS MET XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pioglitazone
Clinical Considerations
Abnormal blood glucose concentrations during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality. Most experts recommend the use of insulin during pregnancy to maintain blood glucose concentrations as close to normal as possible for patients with diabetes.
Animal Data
In animal reproductive studies, pregnant rats and rabbits received pioglitazone at doses up to approximately 17 (rat) and 40 (rabbit) times the maximum recommended human oral dose (MRHD) based on body surface area (mg/m2); no teratogenicity was observed. Increases in embryotoxicity (increased postimplantation losses, delayed development, reduced fetal weights, and delayed parturition) occurred in rats that received oral doses approximately 10 or more times the MRHD (mg/m2 basis). No functional or behavioral toxicity was observed in rat offspring. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in rat offspring at oral maternal doses approximately two or more times the MRHD (mg/m2 basis). In rabbits, embryotoxicity occurred at oral doses approximately 40 times the MRHD (mg/m2 basis).
Metformin hydrochloride
Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times a human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, metformin should not be used during pregnancy unless clearly needed.
Labor and Delivery
The effect of ACTOPLUS MET XR on labor and delivery in humans is not known.
Nursing Mothers
No studies have been conducted with the combined components of ACTOPLUS MET XR. 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 are secreted in human milk. Because many drugs are excreted in human milk and because of the potential for ACTOPLUS MET XR to cause serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue ACTOPLUS MET XR, taking into account the importance of ACTOPLUS MET XR to the mother.
Pediatric Use
Safety and effectiveness of ACTOPLUS MET XR in pediatric patients have not been established.
ACTOPLUS MET XR is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors [see Warnings and Precautions (5.1, 5.3, 5.6, 5.7)].
Geriatric Use
Pioglitazone
A total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16- to 26-week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16- to 24-week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥65 years old and 22 (2.1%) were ≥75 years old.
In PROactive, 1068 patients (41.0%) treated with pioglitazone were ≥65 years old and 42 (1.6%) were ≥75 years old.
In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients [see Clinical Pharmacology ].
Although clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥75 years old.
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 XR should only be used in patients with normal renal function [see Contraindications (4), Warnings and Precautions (5.2) and Clinical Pharmacology]. Because aging is associated with reduced renal function, ACTOPLUS MET XR 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 XR [see Warnings and Precautions and Dosage and Administration (2)].
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