KOMBIGLYZE XR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for KOMBIGLYZE XR (KOMBIGLYZE XR).
KOMBIGLYZE XR is a combination of saxagliptin, a DPP-4 inhibitor, and metformin, an AMPK activator. Saxagliptin increases incretin levels (GLP-1, GIP) by inhibiting DPP-4, leading to increased insulin release and decreased glucagon secretion. Metformin decreases hepatic gluconeogenesis and increases peripheral insulin sensitivity.
| Metabolism | Saxagliptin is metabolized via CYP3A4/5 to an active metabolite. Metformin is not metabolized and is excreted unchanged in urine. |
| Excretion | Renal excretion of unchanged saxagliptin (24%) and its active metabolite 5-hydroxy saxagliptin (22%); fecal excretion of parent (0.3%) and metabolite (6%); total renal elimination accounts for approximately 75% of the administered dose. |
| Half-life | Terminal elimination half-life for saxagliptin is 2.5 hours and for its active metabolite is 3.1 hours; clinical context: no significant accumulation at steady state. |
| Protein binding | Saxagliptin is approximately 20% bound to plasma proteins; its active metabolite is approximately 30% bound. |
| Volume of Distribution | Volume of distribution (Vd/F) is approximately 1.0 L/kg for saxagliptin, indicating extensive extravascular distribution. |
| Bioavailability | Oral bioavailability of saxagliptin is approximately 75% (range 50-80%); not significantly affected by food. |
| Onset of Action | Peak plasma concentrations for saxagliptin achieved within 2 hours; clinical effect on postprandial glucose begins within 30 minutes after oral administration. |
| Duration of Action | Duration of DPP-4 inhibition >12 hours; supports once-daily dosing for glycemic control over 24 hours. |
| Molecular Weight | 497.48 |
| Brand Substitutes | Riax-M XR 5mg/1000mg Tablet |
One tablet orally once daily with food; available strengths: saxagliptin 5 mg/metformin extended-release 500 mg, saxagliptin 5 mg/metformin extended-release 1000 mg. Titrate based on glycemic response and tolerability.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | Contraindicated if eGFR <30 mL/min/1.73 m². No dose adjustment required for eGFR ≥30 mL/min/1.73 m². Assess renal function prior to initiation and periodically. |
| Liver impairment | Not recommended for use in patients with hepatic impairment due to lack of data; use with caution in Child-Pugh class A, B, or C. |
| Pediatric use | Safety and efficacy not established in pediatric patients under 18 years. |
| Geriatric use | Initiate at low dose of metformin component (500 mg once daily); monitor renal function due to age-related decline; increased risk of lactic acidosis in elderly with reduced renal function. |
| 1st trimester | Avoid use due to limited safety data and potential risk of fetal harm. Insulin is preferred for glycemic control. |
| 2nd trimester | Avoid use; consider insulin therapy during pregnancy. |
| 3rd trimester | Avoid use; risk of neonatal hypoglycemia if used near term. Insulin is preferred. |
Clinical note
Comprehensive clinical and safety monograph for KOMBIGLYZE XR (KOMBIGLYZE XR).
| Placental transfer | Metformin crosses the placenta; saxagliptin is likely to cross based on molecular weight. Limited data suggest fetal exposure. |
| Breastfeeding | Excretion into human milk is unknown; however, saxagliptin and metformin, the components of Kombiglyze XR, are excreted. Use caution, especially in nursing infants with renal impairment. |
| Lactation Rating |
■ FDA Black Box Warning
Lactic acidosis: Metformin accumulation can cause lactic acidosis, which is fatal in ~50% of cases. Risk factors include renal impairment, hypoperfusion, sepsis, hepatic impairment, and alcohol abuse.
| Serious Effects |
Severe renal impairment (eGFR <30 mL/min/1.73 m²)Acute or chronic metabolic acidosis, including diabetic ketoacidosisHypersensitivity to saxagliptin, metformin, or any component
| Precautions | Lactic acidosis risk, Pancreatitis, Heart failure (saxagliptin increases risk of hospitalization), Renal impairment (monitor renal function), Hypoglycemia when used with sulfonylureas or insulin, Vitamin B12 deficiency (long-term metformin use), Hypersensitivity reactions |
| Food/Dietary | Take with food to reduce metformin GI upset. Avoid excessive alcohol consumption (≥3 drinks/day) due to increased risk of lactic acidosis. No specific food restrictions otherwise; consistent carbohydrate intake advised. |
Loading safety data…
| L3 (Moderately Safe) - potential infant risk exists; weigh benefits against risks. |
| Teratogenic Risk | FDA Pregnancy Category B. First trimester: Animal studies did not demonstrate teratogenic effects for metformin or saxagliptin. Second and third trimesters: Limited human data; metformin crosses placenta but no increased risk of major congenital anomalies. Saxagliptin has insufficient human data; avoid unless benefit outweighs risk. |
| Fetal Monitoring | Monitor maternal blood glucose, HbA1c, and renal function. Fetal monitoring includes ultrasound for growth and amniotic fluid assessment. Assess for neonatal hypoglycemia and respiratory distress after delivery. |
| Fertility Effects | No known adverse effects on fertility in animal studies with metformin or saxagliptin. In humans, metformin may improve ovulation in women with polycystic ovary syndrome. Limited data on saxagliptin. |
| Clinical Pearls | KOMBIGLYZE XR (saxagliptin/metformin ER) contraindicated in eGFR <30 mL/min/1.73m2; assess renal function before initiation and periodically. Saxagliptin component associated with increased risk of hospitalization for heart failure in patients with prior CV or renal disease. Avoid in patients with history of pancreatitis. Metformin component carries risk of lactic acidosis; discontinue if hypoperfusion, sepsis, or hepatic impairment. No need to adjust dose for mild hepatic impairment. |
| Patient Advice | Take once daily with the evening meal to reduce GI side effects. · Swallow tablets whole; do not crush, cut, or chew. · Monitor for symptoms of lactic acidosis: unusual muscle pain, difficulty breathing, stomach discomfort, dizziness, feeling cold, or slow/irregular heartbeat. · Report symptoms of pancreatitis: severe abdominal pain that may radiate to the back, nausea, vomiting. · For patients with heart failure risk, watch for shortness of breath, fatigue, swelling in ankles/feet. · Check blood sugar regularly; carry glucose source for hypoglycemia. · Do not drink excessive alcohol; may increase lactic acidosis risk. · Use contraception if of childbearing potential; not recommended during pregnancy. · Tell all healthcare providers you take this medication before any procedure requiring contrast dye or surgery. |