REZULIN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for REZULIN (REZULIN).
Rezulin (troglitazone) is a thiazolidinedione that improves insulin sensitivity in peripheral tissues and liver by activating peroxisome proliferator-activated receptor gamma (PPAR-gamma), leading to increased glucose uptake and reduced gluconeogenesis.
| Metabolism | Primarily metabolized by CYP3A4 and CYP2C8; also undergoes sulfation and glucuronidation. |
| Excretion | Primarily hepatic metabolism (CYP3A4) to inactive metabolites; renal excretion of metabolites accounts for approximately 60%, with 30% in feces and 10% unchanged in urine. |
| Half-life | Terminal elimination half-life is 16–34 hours; with accumulation, effective half-life after multiple doses is 3–4 days due to enterohepatic recirculation. |
| Protein binding | >99% bound, primarily to albumin. |
| Volume of Distribution | Approximately 0.3 L/kg; suggests distribution mainly into extracellular fluid and some tissue binding. |
| Bioavailability | Oral bioavailability is approximately 80% (range 70–90%), complete absorption with food slightly increasing rate and extent. |
| Onset of Action | Oral: 30–60 minutes to lower blood glucose; maximal effect on insulin sensitivity occurs after 2–4 weeks of continuous dosing. |
| Duration of Action | Single dose: glucose-lowering effect persists 12–24 hours; with chronic dosing, enhanced insulin sensitivity lasts up to 24 hours post-dose, requiring once-daily administration. |
200-600 mg orally once daily
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for renal impairment; however, troglitazone is not dialyzable, and caution is advised in severe impairment due to lack of data. |
| Liver impairment | Contraindicated in patients with active liver disease or ALT >1.5 times upper limit of normal (ULN). For Child-Pugh Class A, B, or C: use is not recommended due to hepatotoxicity risk. |
| Pediatric use | Safety and efficacy not established in pediatric patients under 18 years. |
| Geriatric use | No specific dose adjustment recommended. Start at lower end of dosing range (200 mg daily) due to increased risk of hepatic adverse effects and fluid retention. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for REZULIN (REZULIN).
| Breastfeeding | Excretion into human breast milk is unknown. Troglitazone is highly protein-bound (>99%) and has a large volume of distribution, suggesting minimal transfer into milk, but no M/P ratio has been established. Due to the potential for serious adverse effects in nursing infants, including hepatotoxicity, breastfeeding is contraindicated during therapy and for at least one week after the last dose. |
| Teratogenic Risk | Troglitazone (Rezulin) is classified as Pregnancy Category C. Animal studies have shown embryotoxicity and fetotoxicity at doses 0.5-2 times the human exposure based on AUC. There are no adequate and well-controlled studies in pregnant women. First trimester exposure may be associated with increased risk of miscarriage; however, specific teratogenic effects in humans are not well-documented. Given its hepatotoxicity profile, use in pregnancy is not recommended. |
■ FDA Black Box Warning
WARNING: Hepatotoxicity. Troglitazone has been associated with severe and potentially fatal liver injury. Patients should be monitored for signs of liver injury, such as jaundice, dark urine, or elevated liver enzymes. Troglitazone should not be used in patients with active liver disease or elevated liver enzymes (ALT > 2.5 times the upper limit of normal).
| Serious Effects |
Known hypersensitivity to troglitazone, active liver disease, elevated liver enzymes (ALT > 2.5 times upper limit of normal), type 1 diabetes, diabetic ketoacidosis.
| Precautions | Hepatotoxicity: Monitor liver enzymes before and during therapy. Avoid in patients with active liver disease or ALT > 2.5x ULN. Discontinue if jaundice or ALT > 3x ULN occurs. Edema: May cause fluid retention, especially when used with insulin. Use caution in patients with heart failure. Hypoglycemia: Risk when used with insulin or sulfonylureas. Decreased efficacy over time may occur. |
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| Fetal Monitoring | Monitor liver function tests (ALT, AST) before initiation and monthly thereafter. Discontinue if ALT >3 times upper limit of normal or if jaundice occurs. In pregnancy, monitor for signs of hepatic toxicity and fetal growth abnormalities via ultrasound if exposure occurs. No specific fetal monitoring guidelines exist due to lack of data. |
| Fertility Effects | Troglitazone may improve ovulatory function in women with polycystic ovary syndrome (PCOS) by reducing insulin resistance and hyperandrogenism, thereby restoring fertility. No adverse effects on fertility have been reported in animal studies at clinically relevant doses. |