Alogliptin-Metformin (alogliptin benzoate/metformin HCl)

Alogliptin benzoate, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is an antidiabetic agent.

Metformin hydrochloride is a biguanide antidiabetic agent.

Alogliptin inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that inactivates the incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Alogliptin selectively inhibits DPP-4 with no effect on DPP-8 or DPP-9 in vitro at concentrations approximating those from therapeutic exposures. Alogliptin increases circulating concentrations 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 elevated). GLP-1 also decreases glucagon secretion from pancreatic alpha-cells, leading to reduced hepatic glucose production.

Alogliptin did not increase the QT interval corrected for rate (QTc) at daily dosages of 50 or 400 mg daily for 7 days in a randomized, placebo-controlled, active-comparator (moxifloxacin) study; the 400-mg dose produced plasma concentrations 19-fold higher than the maximum recommended clinical dose of 25 mg.

Following oral administration of a single dose of alogliptin (up to 800 mg) in healthy individuals, median time to peak plasma concentration was 1-2 hours; the drug has an absolute oral bioavailability of approximately 100%. Peak inhibition of DPP-4 occurs within 1--2 hours of administration with single and repeated dosing in patients with type 2 diabetes mellitus. Administration of alogliptin with food did not substantially alter total and peak exposure to the drug.

Alogliptin does not undergo extensive metabolism; 60-80% of the dose is excreted unchanged. Following administration of a radiolabeled dose of alogliptin, approximately 89% of administered radioactivity was excreted in urine (76%) and feces (13%). Terminal elimination half-life of alogliptin is approximately 21 hours following a single dose of 25 mg.

Age (range: 18--80 years), gender, and race do not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Total and peak exposure to alogliptin are approximately 10% and 8% lower, respectively, in patients with moderate hepatic impairment (Child-Pugh class B); the effects of severe hepatic impairment (Child-Pugh class C) have not been studied. Exposure (as determined by plasma AUC) is increased 1.2-fold in patients with mild renal impairment (creatinine clearance >=60 to 90 mL/minute), 2-fold in patients with moderate renal impairment (creatinine clearance >=30 to <60 mL/minute), 3-fold in patients with severe renal impairment (creatinine clearance >=15 to <30 mL/minute), and 4-fold in patients with end-stage renal disease (creatinine clearance <15 mL/minute or requiring dialysis).

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: This combination medication 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: alogliptin and metformin. Alogliptin 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 works by helping to restore your body's proper response to the insulin you naturally produce. It also decreases the amount of sugar that your liver makes and that your stomach/intestines absorb.

Generic name: alogliptin benzoate/metformin HCl
Pronunciation: (AL-oh-GLIP-tin/met-FOR-min)

The following indications are listed for Alogliptin-Metformin:

• 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.