KAZANO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for KAZANO (KAZANO).
Kazano is a combination of alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin, a biguanide. Alogliptin inhibits DPP-4, increasing incretin levels (GLP-1 and GIP), which enhances glucose-dependent insulin secretion and suppresses glucagon release. Metformin decreases hepatic glucose production, reduces intestinal glucose absorption, and improves insulin sensitivity.
| Metabolism | Metformin is not metabolized; excreted unchanged in urine. Alogliptin is minimally metabolized; major enzyme is CYP2D6 (minor contribution) and CYP3A4 (minor). Elimination primarily renal as unchanged drug. |
| Excretion | Metformin: ~90% unchanged via renal (glomerular filtration and tubular secretion). Alogliptin: ~76% unchanged renal, ~13% fecal. Approximately 89% of total clearance is renal for alogliptin. |
| Half-life | Metformin: terminal elimination half-life ~6.2 hours (plasma), prolonged to ~17.6 hours in renal impairment. Alogliptin: terminal elimination half-life ~21 hours, allowing once-daily dosing. |
| Protein binding | Metformin: negligible (<5%), not bound to plasma proteins. Alogliptin: ~20% bound to plasma proteins (primarily albumin), concentration-independent. |
| Volume of Distribution | Metformin: 654 ± 358 L (about 9.3 L/kg based on 70 kg, suggesting extensive tissue distribution). Alogliptin: 87-104 L (about 1.2-1.5 L/kg), indicating distribution into total body water. |
| Bioavailability | Metformin: absolute bioavailability ~50-60% (tablet). Alogliptin: absolute bioavailability ~100% (oral tablet). |
| Onset of Action | Metformin: onset within 1-3 days for glycemic effect, maximal effect in 1-2 weeks. Alogliptin: onset within 1-2 hours for DPP-4 inhibition, clinical glycemic effects observed within 1 week. |
| Duration of Action | Metformin: duration ~24 hours due to extended release formulation; usual dosing once or twice daily. Alogliptin: duration >24 hours (sustained DPP-4 inhibition >80% at 24 hours), supporting once-daily dosing. |
Oral: 1 tablet (alogliptin 12.5 mg / metformin 500 mg) twice daily with meals. Maximum dose: alogliptin 25 mg / metformin 2000 mg per day.
| Dosage form | TABLET |
| Renal impairment | eGFR 30-44 mL/min: maximum alogliptin 12.5 mg / metformin 500 mg once daily. eGFR <30 mL/min: contraindicated. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B or C: not recommended due to lack of data. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | Initiate at lowest dose; monitor renal function. Avoid in patients aged ≥80 years unless eGFR >45 mL/min. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for KAZANO (KAZANO).
| Breastfeeding | No human data. Metformin is excreted into breast milk with M/P ratio 0.35-0.64. Alogliptin unknown. Avoid breastfeeding due to risk of infant hypoglycemia and potential renal effects. |
| Teratogenic Risk | FDA Pregnancy Category C. In first trimester, no adequate human data; animal studies show no teratogenicity but may cause fetal renal toxicity. In second and third trimesters, metformin and alogliptin have limited data; risk of fetal renal impairment due to metformin accumulation. Alogliptin not teratogenic in animals. |
■ FDA Black Box Warning
Lactic acidosis: Metformin-associated lactic acidosis can occur due to metformin accumulation. Risk factors include renal impairment, concomitant use of certain drugs (e.g., topiramate, acetazolamide), age ≥65 years, radiological studies with contrast, surgery, hepatic impairment, acute alcohol intake, and hypoxic states. Discontinue metformin if lactic acidosis is suspected.
| Serious Effects |
["Severe renal impairment (eGFR <30 mL/min/1.73 m2)","Acute or chronic metabolic acidosis, including diabetic ketoacidosis","Hypersensitivity to alogliptin, metformin, or any component of the product","History of serious hypersensitivity reaction to DPP-4 inhibitors"]
| Precautions | ["Lactic acidosis (see black box warning)","Pancreatitis: Acute pancreatitis reported; discontinue if suspected.","Heart failure: Consider risks/benefits; DPP-4 inhibitors may increase heart failure risk.","Hypoglycemia: Risk when combined with insulin or insulin secretagogues; dose adjustment may be needed.","Renal impairment: Assess renal function before initiation and periodically; contraindicated in eGFR <30 mL/min/1.73 m2.","Vitamin B12 deficiency: Metformin may decrease B12 levels; monitor.","Hypersensitivity reactions: Serious allergic reactions reported, including anaphylaxis and severe cutaneous adverse reactions.","Arthralgia: Severe joint pain reported with DPP-4 inhibitors."] |
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| Fetal Monitoring |
| Monitor maternal renal function (serum creatinine, eGFR) and blood glucose. Fetal surveillance: ultrasound for renal development and growth. Monitor for neonatal hypoglycemia after delivery. |
| Fertility Effects | No known adverse effects on fertility in males or females. Metformin may improve ovulatory function in women with PCOS. Alogliptin has no reported fertility effects. |
| Food/Dietary | Avoid excessive alcohol consumption due to increased risk of lactic acidosis with metformin. No specific food restrictions with empagliflozin. Maintain consistent carbohydrate intake to minimize blood glucose variability. Metformin absorption may be reduced by high-fat meals; take with food to improve tolerability. |
| Clinical Pearls | KAZANO is a fixed-dose combination of empagliflozin and metformin. Monitor renal function before initiation and periodically; eGFR should be ≥45 mL/min/1.73 m² for empagliflozin and ≥30 mL/min/1.73 m² for metformin. Evaluate for lactic acidosis if metformin accumulation risk. Check volume status in elderly or those on diuretics. Assess for ketoacidosis even with normal glucose. Avoid in severe hepatic impairment. |
| Patient Advice | Take with meals to reduce gastrointestinal upset from metformin. · Stay well hydrated to prevent dehydration and kidney issues. · Report symptoms of urinary tract infections or genital mycotic infections. · Seek immediate medical attention for signs of lactic acidosis (e.g., unusual muscle pain, difficulty breathing, severe tiredness). · Monitor blood glucose regularly and be aware of signs of hypoglycemia, especially if used with sulfonylureas or insulin. · Do not change dose or stop without consulting healthcare provider. · Inform all healthcare providers that you are taking this medication. |