Duetact Disease Interactions

The use of oral hypoglycemic agents may be associated with an increased risk of cardiovascular mortality compared to treatment with diet alone or diet with insulin. This warning is based on the University Group Diabetes Program (UGDP) study, a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. Patients treated with diet plus a fixed dosage of either tolbutamide (a sulfonylurea) or phenformin (a biguanide) for 5 to 8 years had a cardiovascular mortality rate approximately 2.5 times that of patients treated with diet alone, resulting in discontinuation of both these treatments in the study. Despite controversy regarding interpretation of these results, clinicians and patients should be aware of the potential risk when making treatment decisions for diabetes, particularly in the presence of underlying cardiovascular disease. Data are not available for other sulfonylureas or biguanides, nor for hypoglycemic agents belonging to other classes. However, given the similarities in chemical structure and/or mode of action, the same caution should be applied.

Sulfonylureas are metabolized in the liver, and their metabolites (some with pharmacologic activity) are excreted in the urine and feces. Patients with impaired liver and/or renal function treated with sulfonylureas may be exposed to higher serum drug concentrations, which can increase the potential for severe hypoglycemic episodes induced by these agents. In the presence of hepatic impairment, gluconeogenic capacity may also be diminished, further compounding the risk. Therapy with sulfonylureas should be administered cautiously in patients with liver and/or renal disease. Reduced dosages and longer intervals between dosage adjustments may be required. Hypoglycemia, if it occurs during treatment, may be prolonged in these patients because of slowed metabolism and/or excretion of the drugs.

The use of thiazolidinediones, alone or in combination with other antidiabetic agents, has been associated with fluid retention and new onset or exacerbation of heart failure. An increased risk of cardiovascular events (heart failure worsening; new or worsening edema; new or worsening dyspnea; increases in heart failure medication; myocardial infarction; angina; cardiovascular hospitalization and deaths) has been reported with rosiglitazone therapy in type II diabetic patients with New York Heart Association (NYHA) Class I or II congestive heart failure compared to placebo. Likewise, overnight hospitalization for CHF was observed in 9.9% of diabetic patients with NYHA Class II and III heart failure on pioglitazone compared to 4.7% of patients on glyburide. An increased incidence of cardiovascular adverse events including edema and cardiac failure has also been reported in patients receiving a thiazolidinedione in combination with insulin relative to insulin and placebo. Therapy with thiazolidinediones should be administered cautiously and initiated at the lowest recommended dosage in patients with congestive heart failure. Thiazolidinediones are contraindicated for the treatment of patients with NYHA Class III or IV cardiac status. Patients should be monitored for signs of worsening heart failure such as increased dyspnea, edema, and weight gain. Therapy should be discontinued if any deterioration in cardiac status occurs.

Thiazolidinediones exert their hypoglycemic effect only in the presence of insulin. Therefore, these agents should not be used in patients with type I diabetes or for the treatment of diabetic ketoacidosis.

Hypoglycemia may commonly occur during treatment with insulin and/or oral hypoglycemic agents. Care should be taken in patients who may be particularly susceptible to the development of hypoglycemic episodes during the use of these drugs, including those who are debilitated or malnourished, those with defective counterregulatory mechanisms (e.g., autonomic neuropathy and adrenal or pituitary insufficiency), and those receiving beta-adrenergic blocking agents.

There are insufficient data to determine if pioglitazone has an effect on preexisting bladder tumors or if it can cause bladder cancer. However, the manufacturer does not recommend the use of pioglitazone in patients with active bladder cancer. In patients with history of bladder cancer the benefit of treatment versus the risk of cancer recurrence during treatment should be considered.

Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Therapy with these agents should be used with caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative. There have been postmarketing reports of hemolytic anemia in patients receiving these drugs who did not have known G6PD deficiency.

Treatment with sulfonylureas may cause hyponatremia, in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain sulfonylureas and these drugs may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH. Caution should be used when treating patients with hyponatremia or at greater risk of developing hyponatremia such as elderly patients, patients taking diuretics or those who are volume-depleted.

Thiazolidinediones can cause dose-related edema. Therapy with thiazolidinediones should be administered cautiously in patients at risk for congestive heart failure as well as those with fluid overload or other conditions that may be adversely affected by excess fluid such as hypertension. Patients should be monitored for signs and symptoms of heart failure such as dyspnea, swelling of legs or ankles, and weight gain.

Initiation of rosiglitazone or pioglitazone therapy is not recommended in patients who exhibit clinical evidence of active liver disease or increased baseline serum transaminase levels (ALT exceeding 2.5 times upper limit of normal). Use of these agents is also not recommended in patients who have experienced jaundice during treatment with troglitazone. The use of troglitazone, another agent in the thiazolidinedione class, has been associated with clinically significant elevations in liver enzymes, reversible jaundice, and idiosyncratic hepatocellular injury including rare cases of liver failure, liver transplants, and death. Injury has occurred after both short- and long-term treatment. While these effects have not been associated with other thiazolidinediones in clinical trials, concerns exist because of their structural similarities. In addition, isolated cases of hepatitis and hepatic enzyme elevations to 3 or more times the upper limit of normal have been reported with both rosiglitazone and pioglitazone during postmarketing use. Rarely, these events have involved hepatic failure with and without fatal outcome, although causality has not been established. Until more safety data are available, patients who are prescribed thiazolidinedione therapy should have serum transaminase levels checked at baseline and periodically thereafter as clinically necessary. Mild to moderate elevations (ALT less than or equal to 2.5 times ULN) require cautious use with more frequent monitoring to determine if the elevations resolve or worsen. Patients who develop potential symptoms of hepatic injury such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, and dark urine should have liver enzymes checked. Therapy should be withdrawn if ALT is elevated and persists above 3 times ULN or if jaundice develops.

New onset or worsening diabetic macular edema with decreased visual acuity have been reported in postmarketing reports in some diabetic patients who were taking thiazolidinedione drugs. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been 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 their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. 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.

In premenopausal, anovulatory patients with insulin resistance, treatment with thiazolidinediones may result in resumption of ovulation. Due to improved insulin sensitivity, pregnancy can occur if adequate contraception is not used.

Thiazolidinediones can cause dose-related weight gain, which may be undesirable in obese patients attempting to lose weight. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. In postmarketing experience with rosiglitazone, there have been reports of unusually rapid increases in weight, greater than those generally observed in clinical trials. Patients who experience such increases should be assessed for fluid retention and volume-related events such as excessive edema and congestive heart failure.

Thiazolidinediones can cause slight decreases in hemoglobin and hematocrit. In clinical studies, hemoglobin levels were reduced primarily within the first 4 to 12 weeks of therapy but remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects. Nevertheless, caution may be advisable when thiazolidinediones are prescribed to patients with certain anemias.