Piozone Special Precautions

Fluid Retention and Congestive Heart Failure: Like other thiazolidinediones, pioglitazone can cause fluid retention when used alone or in combination with other antidiabetic medicines and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure.
Pioglitazone should be used with caution in patients with existing edema or heart failure. The incidence of heart failure increases in patients with a history of cardiac disease eg, coronary artery disease, previous coronary artery bypass graft procedures and myocardial infarction. Weight gain, usually dose-dependent and probably due to a combination of fluid retention and fat accumulation, has been reported with pioglitazone use. Patients who experience weight gain should be assessed for fluid accumulation and volume-related events eg, excessive edema and congestive heart failure.
Initiate pioglitazone therapy at the lowest approved dose when treating patients who have at least one risk factor for development of congestive heart failure. Monitor patients for signs and symptoms of heart failure and fluid retention. In particular, patients who are at risk for heart failure including those receiving concurrent therapy which increases insulin levels (ie, insulin, sulfonylureas) should be closely monitored (see Adverse Reactions).
Urinary Bladder Tumors: Do not use pioglitazone in patients with active bladder cancer. Use pioglitazone with caution in patients with prior history of bladder cancer. The benefits of blood sugar control with pioglitazone should be weighed against the unknown risk for cancer recurrence.
Results from a 5-year interim analysis of a 10-year observational cohort study showed a small increased risk of bladder cancer in diabetic patients treated with pioglitazone, in particular those who were treated for the longest durations and with the highest cumulative doses. The study suggest that the use of pioglitazone for >1 year increased the relative risk of developing bladder cancer in any given year by 40% (absolute risk of 3 cases in 10,000). Although there is insufficient evidence to determine whether pioglitazone promotes the development of urinary bladder tumors, pioglitazone should not be used in patients with active bladder cancer. In patients with a history of bladder cancer, the benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone should be considered.
Counsel patients to report any signs or symptoms of blood in the urine, urinary urgency, pain on urination, back or abdominal pain, as these may be due to bladder cancer.
Hepatic Effects: Therapy with pioglitazone should not be initiated in patients with increased baseline liver enzyme levels ie, ALT > 2.5 times the upper limit of normal (ULN), or active liver disease.
There have been post-marketing reports of fatal and nonfatal hepatic failure in patients taking pioglitazone. These reports, however, contain insufficient information necessary to establish the probable cause.
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). These patients may also have other forms of liver disease many of which can be treated or managed. It is therefore recommended that prior to therapy with pioglitazone, a liver function test panel [ie, aspartate aminotransferase (AST), alanine aminotransfease (ALT), alkaline phosphatase, and total bilirubin] be obtained and patient be assessed for liver disease. Pioglitazone should be initiated with caution in patients with abnormal liver tests.
Measure liver tests promptly if manifestations suggestive of liver injury (eg, unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine or jaundice) develop in patients receiving pioglitazone. Discontinue pioglitazone therapy if ALT increases to >3 times the ULN during therapy and remains elevated, or if jaundice develops. Patients should be investigated and should not be restarted on pioglitazone without establishing the probable cause of the liver injury.
Do not restart pioglitazone in patients with serum ALT elevations >3 times the ULN and serum total bilirubin >2 times the reference range without alternative etiologies since they are at risk for severe drug-induced liver injury. Initiation of, or continuation of therapy with pioglitazone in patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, should proceed with caution.
Increased Risk of Fracture in Women: In clinical trials, there were more reports of fractures in female patients taking thiazolidinediones, including pioglitazone, than those taking a comparator (either placebo or active). The incidence of bone fracture in females was 5.1% for pioglitazone versus 2.5% for placebo. The difference was noted after the 1st year of treatment and remained during the course of the study. Majority of fractures observed in female patients were nonvertebral fractures including fractures in the distal upper limb (forearm, hand and wrist) or distal lower limb (foot, ankle, fibula, and tibia).
Consider the risk of fracture in the care of patients, especially female patients, being treated with pioglitazone or when starting pioglitazone treatment; attention should be given to assessing and monitoring bone health according to current standards of care.
Hypoglycemia: Use of pioglitazone in combination with insulin and antidiabetic medicines particularly insulin secretagogues eg, sulfonlyureas may increase the risk for hypoglycemia. Reduction in the dose of the concomitant antidiabetic medicine may be necessary.
Macular Edema: Macular edema, some with blurred vision or decreased visual acuity, has been reported in patients receiving pioglitazone or other thiazolidinediones. Most patients reported concurrent peripheral edema. In some patients, macular edema improved after discontinuation of thiazolidinedione treatment.
Although it is not known whether there is causal relationship between pioglitazone and macular edema, regular eye examination by an ophthalmologist is recommended for all diabetic patients. Promptly report and refer any visual symptom to an ophthalmologist.
Ovulation: Pioglitazone, like other thiazolidinediones, may cause ovulation in anovulatory premenoupausal women with insulin resistance. These women have an increased possibility of pregnancy unless contraceptive methods are initiated.
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone or any other antidiabetic medicine. Pioglitazone should not be prescribed to lower the risk of cardiovascular diseases (ie, myocardial infarction and stroke) or to lower cardiovascular mortality.
Type 1 Diabetes Mellitus or Diabetic Ketoacidosis: Pioglitazone is active only in the presence of endogenous insulin and should therefore not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Hematologic: Pioglitazone may cause dose-related decreases in hemoglobin and hematocrit which usually become evident within the first 3 months of starting treatment. These hematologic effects may be related to plasma volume expansion.
Renal Impairment: There is no information available on the use of pioglitazone in dialysed patients. The use of pioglitazone is not recommended in these patients.
Use in lactation: It is not known whether pioglitazone is excreted in human milk although pioglitazone is secreted in the milk of lactating rats. Pioglitazone should not be administered to breastfeeding women.
Use in children: The safety and efficacy of pioglitazone in children have not been established. Use in patients <18 years old is not recommended.
Use in the elderly: There are no significant differences in the pharmacokinetics, efficacy and safety of pioglitazone between geriatric (≥65 years) and younger patients.