Actoplus Met (Page 5 of 11)

PRECAUTIONS

General: 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 (see WARNINGS, Pioglitazone hydrochloride). 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 (see ADVERSE REACTIONS). 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 (see BOXED WARNING, WARNINGS, Pioglitazone hydrochloride, and PRECAUTIONS, Information for Patients).

Weight Gain: Dose related weight gain was observed with pioglitazone alone and in combination with other hypoglycemic agents (Table 3). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Table 3. Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with Pioglitazone
Control Group pioglitazone 15 mg pioglitazone 30 mg pioglitazone 45 mg
Median(25th /75th percentile) Median(25th /75th percentile) Median(25th /75th percentile) Median(25th /75th percentile)
Note: Trial durations of 16 to 26 weeks
Monotherapy -1.4 (-2.7/0.0)n=256 0.9 (-0.5/3.4)n = 79 1.0 (-0.9/3.4)n=188 2.6 (0.2/5.4)n = 79
Combination Therapy Sulfonylurea -0.5 (-1.8/0.7)n=187 2.0 (0.2/3.2)n=183 3.1 (1.1/5.4)n=528 4.1 (1.8/7.3)n=333
Metformin -1.4 (-3.2/0.3)n=160 N/A 0.9 (-0.3/3.2)n=567 1.8 (-0.9/5.0)n=407
Insulin 0.2 (-1.4/1.4)n=182 2.3 (0.5/4.3)n=190 3.3 (0.9/6.3)n=522 4.1 (1.4/6.8)n=338

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 (see ADVERSE REACTIONS, Laboratory Abnormalities). 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 (see ADVERSE REACTIONS).

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.

Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ACTOPLUS MET or any other anti-diabetic drug.

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