No

Antidiabetic Agent (Thiazolidinedione)

Troglitazone is indicated for the following:

• sulfonylureas in patients who are not adequately controlled with a sulfonylurea alone, or
• a sulfonylurea together with metformin for patients who are not adequately controlled with the combination of a sulfonylurea and metformin or
• insulin in patients who are not adequately controlled with insulin alone

Troglitazone is not indicated as initial therapy or monotherapy in patients with type 2 diabetes

B

Hypersensitivity to troglitazone or any component

Patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during clinical trials. Heart enlargement without microscopic changes has been observed in rodents at exposures exceeding 14 times the AUC of the 400 mg human dose. Caution is advised during the administration of troglitazone to patients with NYHA Class III or IV cardiac status.

Patients on troglitazone who develop jaundice or whose laboratory results indicate liver injury should stop taking the drug. Approximately 2% of patients can expect to stop taking the drug because of elevated liver enzymes.

Because of its mechanism of action, troglitazone is active only in the presence of insulin. Therefore, do not use in type 1 diabetes or for the treatment of diabetic ketoacidosis.

Patients receiving troglitazone in combination with insulin may be at risk for hypoglycemia, and a reduction in the dose of insulin may be necessary.

Across all clinical studies, hemoglobin declined by 3% to 4% in troglitazone-treated patients compared with 1% to 2% with placebo. White blood cell counts also declined slightly in troglitazone-treated patients compared with those treated with placebo. These changes occurred within the first 4-8 weeks of therapy. Levels stabilized and remained unchanged for less than or equal to 2 years of continuing therapy. These changes may be due to the dilutional effects of increased plasma volume and have not been associated with any significant hematologic clinical effects. The FDA, in conjunction with the manufacturer of Rezulin® (troglitazone) has elected to withdraw Rezulin® (troglitazone) from the market. The FDA based its decision on a review of recent safety data concerning Rezulin® and two similar drugs, rosiglitazone (Avandia®) and pioglitazone (Actos™). This review demonstrated that Rezulin is associated with more hepatotoxicity than the other two drugs. Both Avandia® and Actos™, approved in the past year, appear to offer the same benefits as Rezulin® without the same risk.

>10%:

Central nervous system: Headache, pain

Miscellaneous: Infection

1% to 10%:

Cardiovascular: Peripheral edema

Central nervous system: Dizziness

Gastrointestinal: Nausea, diarrhea, pharyngitis

Genitourinary: Urinary tract infection

Neuromuscular & skeletal: Neck pain, weakness

Respiratory: Rhinitis

CYP3A3/4 enzyme substrate; CYP3A3/4 enzyme inducer; CYP2C9, 2C19, and 3A3/4 enzyme inhibitor

Cholestyramine: Concomitant administration of cholestyramine with troglitazone reduces the absorption of troglitazone by 70%; COADMINISTRATION OF CHOLESTYRAMINE AND TROGLITAZONE IS NOT RECOMMENDED.

Oral contraceptives: Administration of troglitazone with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both by 30%. These changes could result in loss of contraception.

Terfenadine: Coadministration of troglitazone with terfenadine decreases plasma concentrations of terfenadine and its active metabolite by 50% to 70% and may reduce the effectiveness of terfenadine

Increased toxicity:

Sulfonylureas (glyburide): Coadministration of troglitazone with glyburide may further decrease plasma glucose levels

Thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion. It has a unique mechanism of action that is dependent on the presence of insulin for activity. Troglitazone decreases hepatic glucose output and increases insulin-dependent glucose disposal in skeletal muscle and possible liver and adipose tissue.

Onset of action: Generally requires >3 weeks

Absorption: Food increases absorption by 30% to 85%

Distribution: V_d:10.5-26.5 L/kg

Protein binding: >99%, to serum albumin

Metabolism: Extensive; troglitazone does induce cytochrome P-450 3A4 metabolism; the inhibitory effect on P-450 isozymes (especially 3A4, 2C9, and 2C19) is believed to not be clinically important and associated with troglitazone concentrations of 11 mcg/mL. NOTE: Concentrations of 1-3 mcg/mL are obtained at 600 mg/day of troglitazone (ie, the maximum adult dosage).

Bioavailability: Absolute

Half-life, plasma elimination: 16-34 hours

Time to peak plasma concentrations: 2-3 hours

Elimination: 85% in feces and 3% in urine

Oral (take with meals):

Combination therapy with insulin: Continue the current insulin dose upon initiation of troglitazone therapy

Initiate therapy at 200 mg once daily in patients on insulin therapy. For patients not responding adequately, increase the dose after 2-4 weeks. The usual dose is 400 mg/day; maximum recommended dose: 600 mg/day.

It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to <120 mg/dL in patients receiving concomitant insulin and troglitazone. Individualize further adjustments based on glucose-lowering response.

Combination therapy with metformin and sulfonylureas: 400 mg once daily

Elderly: Steady-state pharmacokinetics of troglitazone and metabolites in healthy elderly subjects were comparable to those seen in young adults

Dosing adjustment/comments in renal impairment: Dose adjustment is not necessary

Dosing adjustment in hepatic impairment: Troglitazone should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT >1.5 times the upper limit of normal).

Food increases absorption by 30% to 85%

Urine for glucose and ketones, fasting blood glucose, hemoglobin A_1c, and fructosamine. Monitor LFTs prior to start of therapy, monthly for the first year of therapy, and quarterly thereafter. Serum transaminase levels should be tested prior to initiation of troglitazone therapy and then tested monthly during the first year of therapy. Thereafter, liver enzymes should be tested quarterly while on troglitazone therapy. Additionally, liver function tests should be performed on any patient on troglitazone who develops symptoms of liver dysfunction, such as nausea, vomiting, abdominal pain, fatigue, loss of appetite, or dark urine.

Target range: Adults:

Glycosylated hemoglobin: <7%

May cause dizziness

None reported

No information available to require special precautions

Troglitazone-dependent diabetics should be appointed for dental treatment in morning in order to minimize chance of stress-induced hypoglycemia

Take with meals. Follow directions of prescriber. If dose is missed at the usual meal, take it with next meal. Do not double dose if daily dose is missed completely. Monitor urine or serum glucose as recommended by prescriber. More frequent monitoring is required during periods of stress, trauma, surgery, pregnancy, increased activity or exercise. Avoid alcohol. Report chest pain, rapid heartbeat or palpitations, abdominal pain, fever, rash, hypoglycemia reactions, yellowing of skin or eyes, dark urine or light stool, or unusual fatigue or nausea/vomiting. Pregnancy/breast-feeding precautions: Use alternate means of contraception if using oral contraceptives. Breast-feeding is not recommended.

Patients who are NPO may need to have their dose held to avoid hypoglycemia

Tablet: 200 mg, 400 mg