SAXAGLIPTIN AND METFORMIN HYDROCHLORIDE
Clinical safety rating: safe
Strong CYP3A4/5 inhibitors may increase levels May cause hypersensitivity reactions including anaphylaxis.
Saxagliptin inhibits dipeptidyl peptidase-4 (DPP-4), increasing incretin levels (GLP-1, GIP), enhancing glucose-dependent insulin secretion, and suppressing glucagon release. Metformin reduces hepatic gluconeogenesis, decreases intestinal glucose absorption, and improves insulin sensitivity.
| Metabolism | Saxagliptin primarily metabolized by CYP3A4/5. Metformin not metabolized; excreted unchanged in urine. |
| Excretion | Saxagliptin: 75% renal (50% unchanged, 25% as metabolite), 22% fecal. Metformin: 90-100% renal unchanged via tubular secretion. |
| Half-life | Saxagliptin: 2.5 hours; 5-hydroxy saxagliptin (active metabolite): 3.1 hours. Metformin: 4.5-6.2 hours. Total combined half-life 2-6 hours, requiring twice-daily dosing. |
| Protein binding | Saxagliptin: negligible (<10%). 5-hydroxy saxagliptin: negligible. Metformin: <5% (minimal). |
| Volume of Distribution | Saxagliptin: ~3 L/kg. Metformin: 654 L (single dose; ~9.3 L/kg for 70 kg). Distributing widely into tissues (erythrocytes, GI tract, liver). |
| Bioavailability | Saxagliptin: ~67% (oral). Metformin: 40-60% (oral, dose-dependent; decreases with higher doses). |
| Onset of Action | Metformin: 30-60 min (plasma glucose reduction). Saxagliptin: 1-2 hours (DPP-4 inhibition >80% at 2 h). |
| Duration of Action | Saxagliptin: 24 hours (DPP-4 inhibition maintained). Metformin: 8-12 hours (glucose control). Dosed twice daily for sustained efficacy. |
Initial dose: 2.5 mg saxagliptin/500 mg metformin hydrochloride orally twice daily with meals. Titrate up to max 5 mg/1000 mg twice daily.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | Contraindicated if eGFR <30 mL/min/1.73 m2. For eGFR 30-45: do not initiate; if already on, reduce dose to maximum 2.5 mg saxagliptin/500 mg metformin twice daily. Monitor renal function. Discontinue if eGFR falls <30. |
| Liver impairment | Avoid use in patients with hepatic impairment (Child-Pugh class A, B, or C) due to metformin component risk of lactic acidosis. |
| Pediatric use | Not recommended for use in children (safety and efficacy not established in pediatric patients). |
| Geriatric use | Use with caution; initiate at lowest dose; monitor renal function closely due to age-related decline. Avoid if eGFR <30. Titrate slowly to minimize gastrointestinal effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP3A4/5 inhibitors may increase levels May cause hypersensitivity reactions including anaphylaxis.
| FDA category | Animal |
| Breastfeeding | Saxagliptin: Unknown if excreted in human milk; animal studies show presence in milk. Metformin: Excreted into human milk with M/P ratio of approximately 0.35; infant plasma concentrations 0.3-1.5% of maternal weight-adjusted dose; no adverse effects reported in breastfed infants. Caution advised; alternatives preferred. |
| Teratogenic Risk |
■ FDA Black Box Warning
No FDA black box warning.
| Common Effects | Nasopharyngitis |
| Serious Effects |
["Severe renal impairment (eGFR <30 mL/min/1.73m²)","Acute or chronic metabolic acidosis (including diabetic ketoacidosis)","History of serious hypersensitivity reaction to saxagliptin or metformin"]
| Precautions | ["Pancreatitis","Heart failure risk","Acute kidney injury","Lactic acidosis (rare, with metformin)","Vitamin B12 deficiency (metformin)","Hypoglycemia when combined with insulin or sulfonylurea","Hypersensitivity reactions"] |
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| Pregnancy Category X: Saxagliptin: Limited human data; animal studies show no teratogenicity at exposures up to 240-fold human exposure. Metformin: Crosses placenta; associated with reduced birth weight and increased risk of neonatal hypoglycemia; some studies suggest no major malformations. Use contraindicated in pregnancy, particularly during second and third trimesters due to metformin's effects on fetal insulin secretion. |
| Fetal Monitoring | Monitor blood glucose, HbA1c, renal function (serum creatinine, BUN), hepatic enzymes, and signs of lactic acidosis or pancreatitis. In pregnancy, fetal monitoring via ultrasound for growth and amniotic fluid volume. Assess for neonatal hypoglycemia after delivery. |
| Fertility Effects | Saxagliptin: No significant effects on fertility in animal studies. Metformin: May improve ovulation in women with polycystic ovary syndrome; no evidence of impaired fertility in males or females. Limited human data on combination. |