saxagliptin/metformin (Kombiglyze XR)

Dosing and uses of Kombiglyze XR (saxagliptin-metformin)

• Adult
• Pediatric
• Geriatric

 

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