Rosiglitazone

Uses

Rosiglitazone is used

• As monotherapy for glycemic control.
• For use in combination with a sulfonylurea, metformin, or insulin when diet, exercise, and a single agent do not result in adequate glycemic control.
• Also for use in combination with a sulfonylurea plus metformin when diet, exercise, and both agents do not result in adequate glycemic control.

Rosiglitazone is also used to associated treatment for these conditions: Type 2 Diabetes Mellitus

How Rosiglitazone works

Rosiglitazone acts as a highly selective and potent agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, rosiglitazone enhances tissue sensitivity to insulin.

Dosage

Rosiglitazone dosage

The management of antidiabetic therapy should be individualized. Rosiglitazone may be administered either at a starting dose of 4 mg as a single daily dose or divided and administered in the morning and evening. For patients who respond inadequately following 8 to 12 weeks of treatment, as determined by reduction in FPG, the dose may be increased to 8 mg daily as monotherapy or in combination with metformin, sulfonylurea, or sulfonylurea plus metformin. Rosiglitazone may be taken with or without food.

Monotherapy: The usual starting dose of Rosiglitazone is 4 mg administered either as a single dose once daily or in divided doses twice daily. In clinical trials, the 4 mg twice daily regimen resulted in the greatest reduction in FPG and HbA1c.

Combination therapy: When Rosiglitazone is added to existing therapy, the current dose(s) of the agent(s) can be continued upon initiation of Rosiglitazone therapy.

Sulfonylurea: When used in combination with sulfonylurea, the usual starting dose of Rosiglitazone is 4 mg administered as either a single dose once daily or in divided doses twice daily. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased.

Metformin: The usual starting dose of Rosiglitazone in combination with metformin is 4 mg administered as either a single dose once daily or in divided doses twice daily. It is unlikely that the dose of metformin will require adjustment due to hypoglycemia during combination therapy with Rosiglitazone.

Insulin: For patients stabilized on insulin, the insulin dose should be continued upon initiation of therapy with Rosiglitazone. Rosiglitazone should be dosed at 4 mg daily. Doses of Rosiglitazone greater than 4 mg daily in combination with insulin are not currently indicated. It is recommended that the insulin dose be decreased by 10% to 25% if the patient reports hypoglycemia or if FPG concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response.

Sulfonylurea plus metformin: The usual starting dose of Rosiglitazone in combination with a sulfonylurea plus metformin is 4 mg administered as either a single dose once daily or in divided doses twice daily. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased.

Maximum Recommended Dose: The dose of Rosiglitazone should not exceed 8 mg daily, as a single dose or divided twice daily. The 8 mg daily dose has been shown to be safe and effective in clinical studies as monotherapy and in combination with metformin, sulfonylurea, or sulfonylurea plus metformin. Doses of Rosiglitazone greater than 4 mg daily in combination with insulin are not currently indicated. No dosage adjustments are required for the elderly. No dosage adjustment is necessary when Rosiglitazone is used as monotherapy in patients with renal impairment.

Side Effects

The incidence and types of adverse events reported in clinical trials of Rosiglitazone as monotherapy are similar to that of placebo. Overall, the types of adverse experiences reported when Rosiglitazone was used in combination with a sulfonylurea or metformin were similar to those during monotherapy with Rosiglitazone. Events of anemia and edema tended to be reported more frequently at higher doses, and were generally mild to moderate in severity and usually did not require discontinuation of treatment with Rosiglitazone.

Toxicity

Side effects include fluid retention, congestive heart failure (CHF), liver disease

Precaution

Due to its mechanism of action, Rosiglitazone is active only in the presence of endogenous insulin. Therefore, Rosiglitazone should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Rosiglitazone, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. In combination with insulin, thiazolidinediones may also increase the risk of other cardiovascular adverse events. Rosiglitazone should be discontinued if any deterioration in cardiac status occurs. Rosiglitazone should be used with caution in patients with edema. Liver enzymes should be checked prior to the initiation of therapy with Rosiglitazone in all patients and periodically thereafter per the clinical judgement of the healthcare professional. Therapy with Rosiglitazone should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal).

Interaction

In vitro drug metabolism studies suggest that Rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. A decrease in the dose of Rosiglitazone may be needed when gemfibrozil is introduced. Dosage adjustment is also required when administered with rifampin. Rosiglitazone was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine and oral contraceptives.

Food Interaction

• Take with or without food.

[Moderate] GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes.

Hypoglycemia most frequently occurs during acute consumption of alcohol.

Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise.

The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia.

Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion.

By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia.

Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes.

A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis.

Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan.

Alcohol should not be consumed on an empty stomach or following exercise.

Rosiglitazone Hypertension interaction

[Moderate] 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.

Rosiglitazone Drug Interaction

Moderate: ciprofloxacin, insulin glargineUnknown: nifedipine, amphetamine / dextroamphetamine, zolpidem, darbepoetin alfa, aspirin, diltiazem, varenicline, carvedilol, rosuvastatin, tolterodine, diltiazem, fentanyl, tamsulosin, teriparatide, metformin, glyburide / metformin, vardenafil, metoprolol

Rosiglitazone Disease Interaction

Major: myocardial infarction, CHF, type I diabetesModerate: edema, liver disease, macular edema, premenopausal anovulation, weight gainMinor: anemia

Volume of Distribution

• 17.6 L [oral volume of distribution Vss/F]
• 13.5 L [population mean, pediatric patients]
  

Elimination Route

The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in C_max and a delay in T_max (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone may be administered with or without food. Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range.

Half Life

3-4 hours (single oral dose, independent of dose)

Clearance

• Oral clearance (CL) = 3.03 ± 0.87 L/hr [1 mg Fasting]
• Oral CL = 2.89 ± 0.71 L/hr [2 mg Fasting]
• Oral CL = 2.85 ± 0.69 L/hr [8 mg Fasting]
• Oral CL = 2.97 ± 0.81 L/hr [8 mg Fed]
• 3.15 L/hr [Population mean, Pediatric patients]

Elimination Route

Following oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively.

Pregnancy & Breastfeeding use

There are no adequate and well-controlled studies in pregnant women. Rosiglitazone should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Drug-related material was detected in milk from lactating rats. It is not known whether Rosiglitazone is excreted in human milk. Because many drugs are excreted in human milk, Rosiglitazone should not be administered to a nursing woman.

Contraindication

Rosiglitazone is contraindicated in patients with known hypersensitivity to this product or any of its components.

Special Warning

Use in Children: The safety and effectiveness of Rosiglitazone in pediatric patients have not been established.

Storage Condition

Protect from light and moisture. Store in a cool and dry place.

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