saxagliptin/metformin (Kombiglyze XR)
Classes: Antidiabetics, Biguanides/Dipeptyl Peptidase-IV Inhibitors
Dosing and uses of Kombiglyze XR (saxagliptin-metformin)
Adult dosage forms and strengths
saxagliptin/metformin
tablet, extended-release
- 5mg/500mg
- 2.5mg/1000mg
- 5mg/1000mg
Diabetes Mellitus Type 2
Indicated as adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with sitagliptin or metformin and have inadequate glycemic control on sitagliptin or metformin alone
Individualize starting dose based on patient’s current regimen
Adjust dose according to effectiveness and tolerability; not to exceed daily dose of 5 mg/2000 mg
Administer qDay with evening meaL
Inadequately controlled on metformin alone
- 2.5-5 mg/day saxagliptin PO plus current dose of metformin
Inadequately controlled on saxagliptin alone
- 500 mg/day metformin PO plus 5 mg/day PO saxagliptin
Dosage modifications
Coadministration with strong CYP3A4/5 inhibitors: Not to exceed 2.5 mg/day saxagliptin or 1000 mg/day metformin
Hepatic impairment: Do not administer
Renal impairment
- Obtain eGFR before starting metformin
- eGFR <30 mL/min/1.73 m²: Contraindicated
- eGFR 30-45 mL/min/1.73 m²: Not recommended to initiate treatment
- Monitor eGFR at least annually or more often for those at risk for renal impairment (eg, elderly)
- If eGFR falls below 45mL/min/1.73 m² while taking metformin, risks and benefits of continuing therapy should be evaluated
- If eGFR falls below 30 mL/min/1.73 m²: while taking metformin, discontinue the drug
Pediatric dosage forms and strengths
Safety and efficacy not established
Geriatric dosage forms and strengths
Initial and maintenance dosing should be conservative due to possibility of decreased renal function. Adjust dose gradually and conservatively considering effectiveness and tolerability
Inadequately controlled on metformin alone
2.5-5 mg/day saxagliptin PO plus current dose of metformin
Do not administer to patients >80 years before assessing renal function and determined to be normaL
Inadequately controlled on saxagliptin alone
500 mg/day metformin PO plus 5 mg/day PO saxagliptin
Do not administer to patients >80 years before assessing renal function and determined to be normaL
Concomitant administration with strong CYP3A4/5 inhibitors
Not to exceed 2.5 mg/day saxagliptin or 1000 mg/day metformin
Do not administer to patients >80 years before assessing renal function and determined to be normaL
Metformin
Contraindicated in patients with renal impairment, carefully monitor renal function in the elderly and use with caution as age increases
Initial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population
Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients
Saxagliptin
Saxagliptin: In the 6, double-blind, controlled clinical safety and efficacy trials of saxagliptin, 634 (15.3%) of the 4148 randomized patients were 65 years or older, and 59 (1.4%) patients were 75 years or older
No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients
Kombiglyze XR (saxagliptin-metformin) adverse (side) effects
1-10%
Diarrhea (9.6%)
Nausea/vomiting (6.5%)
Headache (6.5%)
Hypoglycemia, saxagliptin (1.6%)
<1%
Rash
Lymphopenia
Postmarketing reports
Severe and disabling arthralgia
Warnings
Black box warnings
Lactic acidosis caused by metformin accumulation (plasma concentration >5 mcg/mL) is a rare but potentially severe consequence; if it occurs, mortality is ~50%
Incidence is rare (~0.03 cases/1000 patient-years with 0.015 fatal cases/100 patient-years)
Patients with CHF requiring pharmacologic management, in particular those with unstable or acute CHF who are at risk of hypoperfusion and hypoxemia, are at an increased risk of lactic acidosis
Risk of lactic acidosis increases with the degree of renal dysfunction and age
Do not start in patients aged 80 years or older unless CrCl demonstrates that renal function is not reduced because these patients are more susceptible to developing lactic acidosis
Promptly withhold metformin with hypoxemia, dehydration, or sepsis
Avoided with clinical or laboratory evidence of hepatic disease
Caution against excessive alcohol intake, either acute or chronic, during metformin therapy because alcohol potentiates the effects of metformin on lactate metabolism
Should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure
The onset of lactic acidosis often is subtle and accompanied by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, increasing somnolence, nonspecific abdominal distress)
DPP-4 inhibitors may cause joint pain that can be severe and disabling; resolves within a month upon discontinuing the drug
Once stabilized on any dose level of metformin, GI symptoms, which are common during initiation of therapy, are unlikely to be drug related; later occurrences of GI symptoms could be due to lactic acidosis or other serious disease
Contraindications
History of serious hypersensitivity (eg, anaphylaxis, angioedema, exfoliative skin conditions)
Severe renal disease: eGFR <30 ml/min/1.73 m²
Acute or chronic metabolic acidosis, including diabetic ketoacidosis (should be treated with insulin)
Cautions
Gradual increase of metformin dose may reduce GI side effects
Metformin may decrease serum vitamin B12 concentration
Do not exceed saxagliptin 2.5 mg/day when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (eg, ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin)
Coadministration of saxagliptin with thiazolidinediones (eg, rosiglitazone, pioglitazone) increases risk for peripheral edema
Inactive tablet ingredients (ie, ghost tablet) may be eliminated in the feces as a soft, hydrated mass
Pancreatitis reported with saxagliptin; monitor for signs and symptoms and discontinue if pancreatitis suspected
Serious hypersensitivity reactions with saxagliptin reported (typically within the first 3 months of therapy)
Caution with history of angioedema
Severe and disabling arthralgia reported in patients taking DPP-4 inhibitors; consider as a possible cause for severe joint pain and discontinue drug if appropriate
Iodinated contrast imaging procedures
- Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
- Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable
Hypoglycemia
- Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol
- Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects
- Insulin secretagogues, such as sulfonylureas, cause hypoglycemia; therefore, when used in combination with saxagliptin, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia
Congestive heart failure (CHF) risks
- In the SAVOR-TIMI 53 trial (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) 16,492 patients with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo
- A higher incidence of hospitalization for CHF was observed in patients treated with saxagliptin compared with those treated with placebo (3.5% vs 2.8%; P=0.007); this increased risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease
- Circulation. 2014 Oct 28;130(18):1579-88
Pregnancy and lactation
Pregnancy category: B
Lactation: unknown whether distributed in breast milk, caution advised
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Kombiglyze XR (saxagliptin-metformin)
Mechanism of action
Saxagliptin: Dipeptidyl peptidase IV (DPP-4) inhibition that results in increased incretin hormones and enhanced glycemic controL
Metformin: Biguanide; acts by decreasing endogenous hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization; improves glucose tolerance and lowers both basal and postprandial plasma glucose
Pharmacokinetics
Half-Life: saxagliptin 2.5-3.1 hr; metformin 6.2 hr (plasma) and 17.6 hr (blood)
Peak Plasma Time: metformin extended-release 4-8 hr
Peak Plasma Concentration: saxagliptin and active metabolite (24 ng/mL, 47 ng/mL)
Protein Bound: negligible for both saxagliptin and metformin
Metabolism: saxagliptin by CYP3A4/5; major active metabolite is also a DPP4 inhibitor (50% as potent); metformin is excreted unchanged in urine and does not undergo hepatic metabolism
Excretion: feces (saxagliptin 22%), urine (saxagliptin 75%; metformin 90%)
Administration
Oral Administration
Administer qDay with evening meaL
Swallow whole, do not chew, cut, or crush