Kombiglyze Xr (saxagliptin HCl/metformin HCl)

Saxagliptin hydrochloride, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is an antidiabetic agent.

Metformin hydrochloride is a biguanide antidiabetic agent.

Saxagliptin inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that inactivates incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both saxagliptin and its active metabolite (5-hydroxy saxagliptin) are more selective for inhibition of DPP-4 than for DPP-8 or DPP-9. Saxagliptin increases circulating levels of GLP-1 and GIP in a glucose-dependent manner.

GLP-1 and GIP stimulate insulin secretion from pancreatic beta-cells in a glucose-dependent manner (i.e., when glucose concentrations are normal or elevated). GLP-1 also decreases glucagon secretion from pancreatic alpha-cells, leading to reduced hepatic glucose production.

Saxagliptin lowers fasting plasma glucose concentrations and reduces glucose excursions following a glucose load or meal in patients with type 2 diabetes mellitus.

Saxagliptin monotherapy usually is not associated with substantial changes in body weight.

Saxagliptin did not produce a clinically meaningful prolongation of the QT interval corrected for rate (QTc) or heart rate at daily dosages up to 40 mg (8 times the maximum recommended human dose) in a randomized, double-blind, placebo-controlled, crossover, active-comparator study using moxifloxacin in healthy individuals.

Following oral administration of a single dose of saxagliptin under fasted conditions, the median time to peak plasma concentration was 2 hours for saxagliptin and 4 hours for 5-hydroxy saxagliptin. The peak plasma concentration and AUC of saxagliptin and its active metabolite increase proportionally in the 2.5--400 mg dosage range. Administration of saxagliptin with a high-fat meal increased the AUC by 27% and delayed the time to peak plasma concentration by approximately 20 minutes.

In vitro binding of saxagliptin and 5-hydroxy saxagliptin to serum proteins is negligible. Metabolism of saxagliptin is principally mediated by cytochrome P-450 (CYP) 3A4 and 3A5 isoenzymes. Mean plasma half-life of saxagliptin or 5-hydroxy saxagliptin is 2.5 or 3.1 hours, respectively.

Saxagliptin is eliminated by both renal and hepatic pathways; following administration of a single radiolabeled dose, 75% of the dose was excreted in urine (including 24% as unchanged drug and 36% as 5-hydroxy saxagliptin). A total of 22% of administered radioactivity was recovered in feces, representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the GI tract. There are no differences in the pharmacokinetics of saxagliptin based on gender, race, or body mass index.

Females have approximately 25% higher exposure to the active metabolite than males, although this is thought unlikely to be of clinical significance; gender does not affect clearance of saxagliptin or its active metabolite.

Bioequivalence between the fixed combination of saxagliptin and extended-release metformin hydrochloride and each agent (saxagliptin and extended-release metformin hydrochloride) given concurrently as separate tablets has been demonstrated; however, the relative bioavailability of the fixed combination of saxagliptin and extended-release metformin hydrochloride and concomitantly administered saxagliptin and immediate-release metformin hydrochloride has not been established. Metformin immediate-release and extended-release tablets have a similar extent of absorption, but peak plasma concentrations of metformin following administration of the drug as extended-release tablets are approximately 20% lower than peak concentrations following administration of the same dose as immediate-release tablets.

Metformin a biguanide antidiabetic agent, lowers both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus. Biguanides usually do not produce hypoglycemia in patients with diabetes and do not affect normal blood glucose concentrations in nondiabetic individuals; metformin, even in excessive dosage, normally does not lower glucose concentrations below euglycemia, although hypoglycemia occasionally may occur with overdosage. Although the precise mechanism(s) by which metformin exerts its antihyperglycemic effect has not been fully established, current evidence suggests that the medication improves both peripheral and hepatic sensitivity to insulin.

Improved insulin sensitivity occurs principally as a result of decreased hepatic glucose production and enhanced insulin-stimulated uptake and utilization of glucose by peripheral tissues (e.g., skeletal muscle, adipocytes); the relative contribution of these mechanisms to the antihyperglycemic effect of metformin has not been fully elucidated. The apparent improvement in peripheral glucose disposal with metformin therapy has been attributed principally to improved metabolism of glucose via nonoxidative (anaerobic) pathways (e.g., glycogen formation in skeletal muscle, postprandial lactate production in splanchnic tissues, lipogenesis in adipose tissue). Metformin reduces basal hepatic glucose production by decreasing gluconeogenesis and possibly glycogenolysis, thereby lowering fasting plasma glucose concentrations.

Although some investigators have suggested that reduction of hepatic glucose production may be the medication's principal antihyperglycemic mechanism, this effect has not been demonstrated in all studies. In vitro studies in hepatocytes indicate that metformin, at concentrations similar to or higher than those observed with therapeutic dosages, enhances insulin-induced suppression of gluconeogenesis and decreases glucagon-stimulated gluconeogenesis. Insulin secretion usually remains unchanged during metformin therapy; fasting insulin concentrations and day-long plasma insulin response remain the same or may even decrease.

The magnitude of the decrease in fasting blood glucose concentrations generally is proportional to the level of fasting baseline hyperglycemia. Metformin also may decrease plasma glucose concentrations by enhancing basal glucose disposal through insulin-independent mechanisms (e.g., a decrease in free fatty acid oxidation), but such effects appear to be modest.

Metformin is slowly and incompletely absorbed from the GI tract, mainly from the small intestine; absorption is complete within 6 hours. The absolute oral bioavailability of the medication under fasting conditions is reported to be approximately 50-60% with metformin hydrochloride doses of 0.5-1.5 g; binding of the medication to the intestinal wall may explain the difference between the amount of medication absorbed (as determined by the urinary and fecal excretion of unchanged drug) and the amount bioavailable in some studies. In single-dose studies with metformin hydrochloride immediate-release tablets at doses of 0.5-1.5 g or 0.85-2.55 g, plasma metformin concentrations did not increase in proportion to increasing doses, suggesting an active saturable absorption process.

Food decreases and slightly delays the absorption of metformin immediate-release tablets; the clinical importance of these effects is unknown. Administration of metformin hydrochloride immediate-release tablets with food reportedly has decreased peak plasma concentrations of the medication by 35-40%, reduced area under the plasma concentration-time curve (AUC) by 20-25%, and delayed time to peak plasma concentration by 35-40 minutes compared with these parameters in fasting individuals receiving this metformin preparation. However, in one study, concomitant administration of the medication as immediate-release tablets with food had a less pronounced effect (average reduction in bioavailability of 10%) on absorption.

Following oral administration of metformin hydrochloride as an extended-release tablet preparation with food, the extent of absorption (as measured by AUC) increased by approximately 50%, but peak plasma concentrations and time to achieve peak plasma concentrations were not altered. However, following administration of another metformin hydrochloride extended-release preparation (Glumetza(R)) with low-fat and high-fat meals, the AUCs increased by 38 and 73%, respectively, compared with those in the fasting state. Following oral administration of metformin hydrochloride as an immediate-release oral solution with food, the extent of absorption (as measured by AUC) increased by approximately 17-21% compared with administration in the fasted state.

Food delayed the time to achieve peak plasma concentrations by 1.4 hours compared with administration in the fasted state. The pharmacokinetics of immediate-release metformin oral solution were not appreciably affected by the fat content of meals. Following administration of a single 500-mg dose of metformin hydrochloride as immediate-release tablets with food in pediatric patients (12-16 years of age) with type 2 diabetes mellitus, mean peak plasma concentrations and AUC differed less than 5% compared with those values in healthy adults; all patients had normal renal function.

In pediatric patients 11-16 years of age receiving a single dose of metformin in fixed combination with glyburide, mean dose-normalized glyburide peak plasma concentration and AUC differed less than 6% from historical values in healthy adults.

Following oral administration of 0.5-1.5 g of metformin hydrochloride as immediate-release tablets in healthy individuals or in patients with type 2 diabetes mellitus, peak plasma drug concentrations usually are attained within 2-4 hours. Following oral administration of a single dose of metformin hydrochloride as extended-release tablets, peak plasma drug concentrations usually are attained within a median of 7 hours. Following administration of a single dose (0.5-2.5 g) of another extended-release preparation (Glumetza(R)), peak plasma drug concentrations usually are attained within 7-8 hours.

Peak plasma concentrations following administration of metformin extended-release tablets are approximately 20% lower than those following administration of the same dose as immediate-release tablets. The extent of absorption of metformin hydrochloride 2 g once daily as extended-release tablets is similar to that following administration of 1 g of the drug twice daily as immediate-release tablets. Steady-state plasma concentrations with usual dosages of metformin hydrochloride as immediate-release tablets (e.g., 1.5-2.55 g daily in 1 to 3 divided doses) are attained within 24-48 hours.

Satisfactory control of blood or plasma glucose concentration may occur within a few days to 1 week following initiation of metformin therapy in patients with type 2 diabetes mellitus, but the maximum antihyperglycemic effect may be delayed for up to 2 weeks. Following discontinuance of metformin therapy, blood glucose concentration increases within 2 weeks.

Bioequivalence has been demonstrated between the fixed combination of metformin and sitagliptin and each agent given concurrently. Bioequivalence also has been demonstrated between the fixed combination of immediate-release metformin and pioglitazone (ActoPlus Met(R)) and each agent (immediate-release metformin (Glucophage(R)) and pioglitazone (Actos(R))) given concurrently. Results of a bioequivalence study indicate that the fixed-combination tablets of immediate-release metformin hydrochloride and canagliflozin are bioequivalent to the corresponding doses of metformin hydrochloride and canagliflozin given as individual tablets under fed conditions.

Bioequivalence between the fixed combination of extended-release metformin hydrochloride and dapagliflozin (Xigduo(R) XR) and each agent (extended-release metformin hydrochloride and dapagliflozin) given concurrently as separate tablets has been demonstrated; however, the relative bioavailability of the fixed combination of extended-release metformin hydrochloride and dapagliflozin (Xigduo(R) XR) and concomitantly administered dapagliflozin and immediate-release metformin hydrochloride has not been established. Bioequivalence between the fixed-combination tablets of immediate-release metformin hydrochloride and empagliflozin and the corresponding doses of metformin hydrochloride and empagliflozin as individual tablets also has been established. In healthy individuals who received the extended-release metformin hydrochloride preparation (Glumetza(R)) in a single-dose crossover study, a 1-g tablet has been shown to be bioequivalent to two 500-mg tablets based on peak plasma concentrations and AUC.

Metformin is distributed rapidly in animals and humans into peripheral body tissues and fluids, particularly the GI tract; the medication also appears to distribute slowly into erythrocytes and into a deep tissue compartment (probably GI tissues). The highest tissue concentrations of metformin (at least 10 times the plasma concentration) occur in the GI tract (e.g., esophagus, stomach, duodenum, jejunum, ileum), with lower concentrations (twice the plasma concentration) occurring in kidney, liver, and salivary gland tissue. The medication distributes into salivary glands with a half-life of about 9 hours.

Metformin concentrations in saliva are 10-fold lower than those in plasma and may be responsible for the metallic taste reported in some patients. Any local effect of metformin on glucose absorption in the GI tract may be associated with the relatively high GI concentrations of the medication compared with those in other tissues. Limited data indicate that metformin is distributed into breast milk in humans.

Metformin is negligibly bound to plasma proteins.

Following oral administration of metformin hydrochloride (0.5-1.5 g) as immediate-release tablets in healthy individuals or in patients with type 2 diabetes mellitus, plasma concentrations decline in a triphasic manner. The principal plasma elimination half-life of metformin averages approximately 6.2 hours; 90% of the medication is cleared within 24 hours in patients with normal renal function. The decline in plasma metformin concentrations is slower after oral than after IV administration, indicating that elimination is absorption rate-limited.

Urinary excretion data and data from whole blood indicate a slower terminal-elimination phase half-life of 8-20 hours (e.g., 17.6 hours) suggesting that the erythrocyte mass may be a compartment of distribution. Metformin is not metabolized in the liver or GI tract and is not excreted in bile; no metabolites of the medication have been identified in humans. Renal elimination of metformin involves glomerular filtration and secretion by the proximal convoluted tubules as unchanged drug.

Renal clearance is approximately 3.5 times greater than creatinine clearance, indicating that tubular secretion is the principal route of metformin elimination. Renal impairment results in increased peak plasma concentrations of metformin, a prolonged time to peak plasma concentration, and a decreased volume of distribution. Renal clearance is decreased in patients with renal impairment (as measured by decreases in creatinine clearance) and, because of reduced renal function with age, in geriatric individuals.

In geriatric individuals, decreased renal and plasma clearance of metformin results in increased plasma concentrations of metformin; volume of distribution remains unaffected. The pharmacokinetics of metformin in patients with normal renal function do not appear to be affected by sex, race, or the presence of diabetes mellitus.

USES: Saxagliptin/metformin is used with a proper diet and exercise program to control high blood sugar in people with type 2 diabetes. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems. Proper control of diabetes may also lessen your risk of a heart attack or stroke.

This product contains 2 medications: saxagliptin and metformin. Saxagliptin works by increasing levels of natural substances called incretins. Incretins help to control blood sugar by increasing insulin release, especially after a meal.

They also decrease the amount of sugar your liver makes. Metformin lowers blood sugar by helping to restore your body's proper response to the insulin. It also decreases the amount of sugar that your liver makes and that your stomach/intestines absorb.

Generic name: saxagliptin HCl/metformin HCl
Pronunciation: (SAX-a-GLIP-tin/met-FOR-min)

The following indications are listed for Kombiglyze Xr:

• Type 2 Diabetes Mellitus

Also known as: Adult Onset Diabetes, Adult Onset Diabetes Mellitus, Adult Onset Dm, Diabetes Mellitus Type 2, Diabetes Mellitus Type Ii, Ketosis-Resistant Diabetes Mellitus, Ketosis-Resistant Dm, Maturity Onset Diabetes, Maturity Onset Diabetes Mellitus, Non-Insulin Dependent Diabetes Mellitus, Non-Insulin-Dependent Diabetes Mellitus, Type Ii Diabetes Mellitus.

No ICD codes are available for this drug.