ROSIGLITAZONE MALEATE AND METFORMIN HYDROCHLORIDE
Clinical safety rating: safe
Strong CYP2C8 inhibitors may increase levels Can cause or exacerbate congestive heart failure and myocardial ischemia.
Rosiglitazone is a thiazolidinedione that activates peroxisome proliferator-activated receptor gamma (PPARγ), increasing insulin sensitivity in adipose tissue, muscle, and liver. Metformin is a biguanide that decreases hepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
| Metabolism | Rosiglitazone is extensively metabolized via N-demethylation and hydroxylation, primarily by CYP2C8. Metformin is excreted unchanged in urine; does not undergo hepatic metabolism. |
| Excretion | Metformin: 90% renal unchanged via tubular secretion; Rosiglitazone: 64% renal (metabolites), 23% fecal. Combined: minimal biliary excretion. |
| Half-life | Metformin: 4-8.7 h (elimination), prolonged in renal impairment; Rosiglitazone: 3-4 h (terminal), slightly longer in hepatic impairment. |
| Protein binding | Metformin: negligible (<5%, not bound to plasma proteins); Rosiglitazone: 99.8% bound (mainly to albumin). |
| Volume of Distribution | Metformin: 1-5 L/kg (large, distributes into tissues); Rosiglitazone: 0.2-0.3 L/kg (moderate, mainly extracellular). |
| Bioavailability | Metformin: 40-60% oral (absolute); Rosiglitazone: 99% oral (high); fixed-dose combination similar to monocomponents. |
| Onset of Action | Oral: Metformin glucose-lowering in 1-3 days, full effect 1-2 weeks; Rosiglitazone insulin-sensitizing in 2-4 weeks, max effect 8-12 weeks. |
| Duration of Action | Metformin: 24 h (twice daily dosing); Rosiglitazone: >24 h (once daily dosing); combined, steady state maintained with twice daily regimen. |
Oral, initial: rosiglitazone 2 mg plus metformin 500 mg twice daily; maximum: rosiglitazone 8 mg plus metformin 2000 mg per day (divided twice daily).
| Dosage form | TABLET |
| Renal impairment | eGFR 30-45 mL/min: maximum metformin 1000 mg/day (divided twice daily). eGFR <30 mL/min: contraindicated. |
| Liver impairment | Child-Pugh class A: no adjustment; Child-Pugh class B or C: contraindicated. |
| Pediatric use | Not established; safety and efficacy not studied in pediatric patients. |
| Geriatric use | Age 80 years and older: do not initiate metformin if eGFR <45 mL/min; monitor renal function regularly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP2C8 inhibitors may increase levels Can cause or exacerbate congestive heart failure and myocardial ischemia.
| FDA category | Animal |
| Breastfeeding | Metformin is excreted into breast milk in low concentrations (M/P ratio ~0.35); rosiglitazone is likely excreted (M/P ratio unknown). Limited human data; potential for hypoglycemia in infant; avoid use while breastfeeding unless benefit outweighs risk. |
| Teratogenic Risk | Rosiglitazone/metformin: Metformin is contraindicated in first trimester due to increased risk of miscarriage and fetal malformations; rosiglitazone is Pregnancy Category C with potential fetal effects (delayed ossification, reduced fetal weight) in animal studies; second/third trimester risk includes fetal insulin dysregulation, macrosomia, and neonatal hypoglycemia if used near term. Both cross placenta. |
■ FDA Black Box Warning
May cause or exacerbate congestive heart failure. Assess cardiovascular risk before initiating. Do not use in patients with NYHA Class III or IV heart failure.
| Common Effects | Weight gain |
| Serious Effects |
["Hypersensitivity to components","NYHA Class III or IV heart failure","Diabetic ketoacidosis (metformin component)","Severe renal impairment (eGFR <30 mL/min/1.73 m²)","Acute or chronic metabolic acidosis","Lactation"]
| Precautions | ["Cardiovascular risk: increased risk of myocardial infarction and cardiovascular mortality","Heart failure: fluid retention leading to or worsening heart failure","Hepatic effects: monitor liver enzymes; rare cases of hepatotoxicity","Lactic acidosis: metformin-associated, especially in renal impairment, hypoxic states, or alcohol abuse","Hypoglycemia: risk when used with insulin or sulfonylureas","Macular edema: reported with thiazolidinediones","Fractures: increased risk in women","Ovulation: resumption in premenopausal anovulatory women leading to unintended pregnancy","Renal impairment: metformin contraindicated if eGFR <30 mL/min/1.73 m²","Iodinated contrast: withhold metformin at time of or prior to procedure; recheck renal function after"] |
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| Fetal Monitoring | Monitor maternal blood glucose, HbA1c, renal function (serum creatinine), liver function tests (LFTs), and fetal growth via ultrasound; assess for signs of lactic acidosis (metformin) and fluid retention/congestive heart failure (rosiglitazone); neonatal monitoring for hypoglycemia, hypocalcemia, and polycythemia if exposed near term. |
| Fertility Effects | Rosiglitazone may improve ovulation in women with polycystic ovary syndrome (PCOS) by reducing insulin resistance; metformin also improves ovulation in PCOS; both drugs have no known adverse effects on female or male fertility in non-PCOS populations. |