These highlights do not include all the information needed to use KOMBIGLYZE XR safely and effectively. See full prescribing information for KOMBIGLYZE XR. KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets Initial U

Lactic acidosis is a rare, but serious,complication that can occur due to metformin accumulation. The risk increaseswith conditions such as sepsis, dehydration, excess alcohol intake, hepaticimpairment, renal impairment, and acute congestive heart failure.

The onset of lactic acidosis is often subtle, accompanied only by nonspecificsymptoms such as malaise, myalgias, respiratory distress, increasing somnolence,and nonspecific abdominal distress.

Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

If acidosis is suspected, KOMBIGLYZE XR should be discontinued and the patient hospitalized immediately. [See Warnings and Precautions (5.1) .]

KOMBIGLYZE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate.[See Clinical Studies (14) .]

KOMBIGLYZE XR should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

KOMBIGLYZE XR has not been studied in combination with insulin.

The dosage of KOMBIGLYZE XR should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability. KOMBIGLYZE XR should generally be administered once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin. The following dosage forms are available:

The recommended starting dose of KOMBIGLYZE XR in patients who need 5 mg of saxagliptin and who are not currently treated with metformin is 5 mg saxagliptin/500 mg metformin extended-release once daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin.

In patients treated with metformin, the dose of KOMBIGLYZE XR should provide metformin at the dose already being taken, or the nearest therapeutically appropriate dose. Following a switch from metformin immediate-release to metformin extended-release, glycemic control should be closely monitored and dosage adjustments made accordingly.

Patients who need 2.5 mg saxagliptin in combination with metformin extended-release may be treated with KOMBIGLYZE XR 2.5 mg/1000 mg. Patients who need 2.5 mg saxagliptin who are either metformin naive or who require a dose of metformin higher than 1000 mg should use the individual components.

The maximum daily recommended dose is 5 mg for saxagliptin and 2000 mg for metformin extended-release.

No studies have been performed specifically examining the safety and efficacy of KOMBIGLYZE XRin patients previously treated with other antihyperglycemic medications and switchedto KOMBIGLYZE XR. Any change in therapy of type 2 diabetes should be undertakenwith care and appropriate monitoring as changes in glycemic control can occur.

Inform patients that KOMBIGLYZE XR tablets must be swallowed whole and nevercrushed, cut, or chewed. Occasionally, the inactive ingredients of KOMBIGLYZE XRwill be eliminated in the feces as a soft, hydrated mass that may resemblethe original tablet.

The maximum recommended dose of saxagliptin is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). For these patients, limit the KOMBIGLYZE XR dose to 2.5 mg/1000 mg once daily. [See Dosage and Administration (2.1) , Drug Interactions (7.1) , and ClinicalPharmacology (12.3) .]

KOMBIGLYZE XR is contraindicated in patients with:

KOMBIGLYZE XR should be temporarily discontinued in patientsundergoing radiologic studies involving intravascular administration of iodinatedcontrast materials because use of such products may result in acute alterationof renal function [see Warnings and Precautions(5.10) ].

Lactic acidosis is a rare, but serious,metabolic complication that can occur due to metformin accumulation duringtreatment with KOMBIGLYZE XR; when it occurs, it is fatal in approximately 50%of cases. Lactic acidosis may also occur in association with a number of pathophysiologicconditions, including diabetes mellitus, and whenever there is significanttissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevatedblood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbanceswith an increased anion gap, and an increased lactate/pyruvate ratio. Whenmetformin is implicated as the cause of lactic acidosis, metformin plasmalevels >5 µg/mL are generally found.

The reported incidenceof lactic acidosis in patients receiving metformin hydrochloride is very low(approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatalcases/1000 patient-years). In more than 20,000 patient-years exposure to metforminin clinical trials, there were no reports of lactic acidosis. Reported caseshave occurred primarily in diabetic patients with significant renal insufficiency,including both intrinsic renal disease and renal hypoperfusion, often in thesetting of multiple concomitant medical/surgical problems and multiple concomitantmedications. Patients with congestive heart failure requiring pharmacologicmanagement, in particular those with unstable or acute congestive heart failurewho are at risk of hypoperfusion and hypoxemia, are at increased risk of lacticacidosis. The risk of lactic acidosis increases with the degree of renal dysfunctionand the patient’s age. The risk of lactic acidosis may, therefore, be significantlydecreased by regular monitoring of renal function in patients taking metforminand by use of the minimum effective dose of metformin. In particular, treatmentof the elderly should be accompanied by careful monitoring of renal function.Metformin treatment should not be initiated in patients ≥80 years of age unlessmeasurement of creatinine clearance demonstrates that renal function is notreduced, as these patients are more susceptible to developing lactic acidosis.In addition, metformin should be promptly withheld in the presence of anycondition associated with hypoxemia, dehydration, or sepsis. Because impairedhepatic function may significantly limit the ability to clear lactate, metforminshould generally be avoided in patients with clinical or laboratory evidenceof hepatic disease. Patients should be cautioned against excessive alcoholintake when taking metformin since alcohol potentiatesthe effects of metformin hydrochloride on lactate metabolism. In addition,metformin should be temporarily discontinued prior to any intravascular radiocontraststudy and for any surgical procedure [see Warningsand Precautions (5.2, 5.5, 5.6, 5.10) ].

The onset oflactic acidosis often is subtle and accompanied only by nonspecific symptomssuch as malaise, myalgias, respiratory distress, increasing somnolence, andnonspecific abdominal distress. There may be associated hypothermia, hypotension,and resistant bradyarrhythmias with more marked acidosis. The patient andthe patient’s physician must be aware of the possible importance of such symptomsand the patient should be instructed to notify the physician immediately ifthey occur [see Warnings and Precautions (5.11) ].Metformin should be withdrawn until the situation is clarified. Serum electrolytes,ketones, blood glucose, and if indicated, blood pH, lactate levels, and evenblood metformin levels may be useful. Once a patient is stabilized on anydose level of metformin, gastrointestinal symptoms, which are common duringinitiation of therapy, are unlikely to be drug related. Later occurrence ofgastrointestinal symptoms could be due to lactic acidosis or other seriousdisease.

Levels of fasting venous plasma lactate abovethe upper limit of normal, but less than 5 mmol/L, in patients taking metformindo not necessarily indicate impending lactic acidosis and may be explainableby other mechanisms, such as poorly controlled diabetes or obesity, vigorousphysical activity, or technical problems in sample handling. [See Warnings and Precautions (5.7) .]

Lacticacidosis should be suspected in any diabetic patient with metabolic acidosislacking evidence of ketoacidosis (ketonuria and ketonemia).

Lacticacidosis is a medical emergency that must be treated in a hospital setting.In a patient with lactic acidosis who is taking metformin, the drug shouldbe discontinued immediately and general supportive measures promptly instituted.Because metformin hydrochloride is dialyzable (with a clearance of up to 170mL/min under good hemodynamic conditions), prompt hemodialysis is recommendedto correct the acidosis and remove the accumulated metformin. Such managementoften results in prompt reversal of symptoms and recovery [see Contraindications (4) and Warningsand Precautions (5.5, 5.6, 5.9, 5.10, 5.11) ].

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Therefore, KOMBIGLYZE XR is contraindicated in patients with renal impairment [see Contraindications (4) ].

Before initiation of KOMBIGLYZE XR, and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and KOMBIGLYZE XR discontinued if evidence of renal impairment is present.

Metformin use in patients with impaired hepatic function has been associated with some cases of lactic acidosis. Therefore, KOMBIGLYZE XR is not recommended in patients with hepatic impairment.

In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B absorption from the B-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on KOMBIGLYZE XR and any apparent abnormalities should be appropriately investigated and managed [see Adverse Reactions (6.1) ].

Certain individuals (those with inadequate vitamin B or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B levels. In these patients, routine serum vitamin B measurements at 2- to 3-year intervals may be useful.

Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving KOMBIGLYZE XR.

Use of KOMBIGLYZE XR should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been eva luated as normal.

A patient with type 2 diabetes previously well controlled on KOMBIGLYZE XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be eva luated promptly for evidence of ketoacidosis or lactic acidosis. eva luation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, KOMBIGLYZE XR must be stopped immediately and other appropriate corrective measures initiated.

Saxagliptin

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. [See AdverseReactions (6.1) .]

Metformin hydrochloride

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. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs.

Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see Drug Interactions(7.2) ], should be used with caution.

Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin [see Contraindications(4) ]. Therefore, in patients in whom any such study is planned, KOMBIGLYZE XR should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-eva luated and found to be normal.

Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on KOMBIGLYZE XR therapy, the drug should be promptly discontinued.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KOMBIGLYZE XR or any other antidiabetic drug.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Metformin hydrochloride

In placebo-controlled monotherapy trials of metformin extended-release, diarrhea and nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting).Diarrhea led to discontinuation of study medication in 0.6% of the patients treated with metformin extended-release.

Saxagliptin

In two placebo-controlled monotherapy trials of 24-week duration, patients were treated with saxagliptin 2.5 mg daily, saxagliptin 5 mg daily, and placebo. Three 24-week, placebo-controlled, add-on combination therapy trials were also conducted: one with metformin immediate-release, one with a thiazolidinedione (pioglitazone or rosiglitazone), and one with glyburide. In these three trials, patients were randomized to add-on therapy with saxagliptin 2.5 mg daily, saxagliptin 5 mg daily, or placebo. A saxagliptin 10 mg treatment arm was included in one of the monotherapy trials and in the add-on combination trial with metformin immediate-release.

Ina prespecified pooled analysis of the 24-week data (regardless of glycemicrescue) from the two monotherapy trials, the add-on to metformin immediate-release trial, theadd-on to thiazolidinedione (TZD) trial, and the add-on to glyburide trial,the overall incidence of adverse events in patients treated with saxagliptin2.5 mg and saxagliptin 5 mg was similar to placebo (72.0% and 72.2% versus70.6%, respectively). Discontinuation of therapy due to adverse events occurredin 2.2%, 3.3%, and 1.8% of patients receiving saxagliptin 2.5 mg, saxagliptin5 mg, and placebo, respectively. The most common adverse events (reportedin at least 2 patients treated with saxagliptin 2.5 mg or at least 2 patientstreated with saxagliptin 5 mg) associated with premature discontinuation oftherapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash(0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%).The adverse reactions in this pooled analysis reported (regardless of investigatorassessment of causality) in ≥5% of patients treated with saxagliptin 5 mg,and more commonly than in patients treated with placebo are shown in Table1.

In patients treated with saxagliptin 2.5 mg, headache (6.5%)was the only adverse reaction reported at a rate ≥5% and more commonly thanin patients treated with placebo.

In this pooled analysis,adverse reactions that were reported in ≥2% of patients treated with saxagliptin2.5 mg or saxagliptin 5 mg and ≥1% more frequently compared to placebo included:sinusitis (2.9% and 2.6% versus 1.6%, respectively), abdominal pain (2.4%and 1.7% versus 0.5%), gastroenteritis (1.9% and 2.3% versus 0.9%), and vomiting(2.2% and 2.3% versus 1.3%).

The incidence rate offractures was 1.0 and 0.6 per 100 patient-years, respectively, for saxagliptin(pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The incidence rateof fracture events in patients who received saxagliptin did not increase overtime. Causality has not been established and nonclinical studies have notdemonstrated adverse effects of saxagliptin on bone.

Anevent of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenicpurpura, was observed in the clinical program. The relationship of this eventto saxagliptin is not known.

Table 2 shows the adverse reactions reported (regardless of investigatorassessment of causality) in ≥5% of patients participating in an additional24-week, active-controlled trial of coadministered saxagliptin and metforminin treatment-naive patients.

In patients treated with the combination of saxagliptin and metformin immediate-release, either as saxagliptin add-on to metformin immediate-release therapy or as coadministration in treatment-naive patients, diarrhea was the only gastrointestinal-related event that occurred with an incidence ≥5% in any treatment group in both studies. In the saxagliptin add-on to metformin immediate-release trial, the incidence of diarrhea was 9.9%, 5.8%, and 11.2% in the saxagliptin 2.5 mg, 5 mg, and placebo groups, respectively. When saxagliptin and metformin immediate-release were coadministered in treatment-naive patients, the incidence of diarrhea was 6.9% in the saxagliptin 5 mg + metformin immediate-release group and 7.3% in the placebo + metformin immediate-release group.

In the saxagliptin clinical trials, adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required. The incidence of reported hypoglycemia for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo given as monotherapy was 4.0% and 5.6% versus 4.1%, respectively. In the add-on to metformin immediate-release trial, the incidence of reported hypoglycemia was 7.8% with saxagliptin 2.5 mg, 5.8% with saxagliptin 5 mg, and 5.0% with placebo. When saxagliptin and metformin immediate-release were coadministered in treatment-naive patients, the incidence of reported hypoglycemia was 3.4% in patients given saxagliptin 5 mg + metformin immediate-release and 4.0% in patients given placebo + metformin immediate-release.

Saxagliptin

Hypersensitivity-related events, such as urticaria and facial edema in the5-study pooled analysis up to Week 24 were reported in 1.5%, 1.5%, and 0.4%of patients who received saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo,respectively. None of these events in patients who received saxagliptin requiredhospitalization or were reported as life-threatening by the investigators.One saxagliptin-treated patient in this pooled analysis discontinued due togeneralized urticaria and facial edema.

Saxagliptin

In the unblinded, controlled, clinical trial database for saxagliptin to date, there have been 6 (0.12%) reports of tuberculosis among the 4959 saxagliptin-treated patients (1.1 per 1000 patient-years) compared to no reports of tuberculosis among the 2868 comparator-treated patients. Two of these six cases were confirmed with laboratory testing. The remaining cases had limited information or had presumptive diagnoses of tuberculosis. None of the six cases occurred in the United States or in Western Europe. One case occurred in Canada in a patient originally from Indonesia who had recently visited Indonesia. The duration of treatment with saxagliptin until report of tuberculosis ranged from 144 to 929 days. Post-treatment lymphocyte counts were consistently within the reference range for four cases. One patient had lymphopenia prior to initiation of saxagliptin that remained stable throughout saxagliptin treatment. The final patient had an isolated lymphocyte count below normal approximately four months prior to the report of tuberculosis. There have been no spontaneous reports of tuberculosis associated with saxagliptin use. Causality has not been established and there are too few cases to date to determine whether tuberculosis is related to saxagliptin use.

There has been one case of a potential opportunistic infection in the unblinded, controlled clinical trial database to date in a saxagliptin-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of saxagliptin therapy. There have been no spontaneous reports of opportunistic infections associated with saxagliptin use.

Saxagliptin

No clinically meaningful changes in vital signs have been observed in patientstreated with saxagliptin alone or in combination with metformin.

Saxagliptin

There was a dose-related mean decrease in absolute lymphocyte count observedwith saxagliptin. From a baseline mean absolute lymphocyte count of approximately2200 cells/microL, mean decreases of approximately 100 and 120 cells/microLwith saxagliptin 5 mg and 10 mg, respectively, relative to placebo were observedat 24 weeks in a pooled analysis of five placebo-controlled clinical studies.Similar effects were observed when saxagliptin 5 mg and metformin were coadministered in treatment-naive patients compared to placebo and metformin. There was no difference observedfor saxagliptin 2.5 mg relative to placebo. The proportion of patients whowere reported to have a lymphocyte count ≤750 cells/microL was 0.5%, 1.5%,1.4%, and 0.4% in the saxagliptin 2.5 mg, 5 mg, 10 mg, and placebo groups,respectively. In most patients, recurrence was not observed with repeatedexposure to saxagliptin although some patients had recurrent decreases uponrechallenge that led to discontinuation of saxagliptin. The decreases in lymphocytecount were not associated with clinically relevant adverse reactions.

Theclinical significance of this decrease in lymphocyte count relative to placebois not known. When clinically indicated, such as in settings of unusual orprolonged infection, lymphocyte count should be measured. The effect of saxagliptinon lymphocyte counts in patients with lymphocyte abnormalities (e.g., humanimmunodeficiency virus) is unknown.

Saxagliptin

Saxagliptin did not demonstrate a clinically meaningful or consistent effecton platelet count in the six, double-blind, controlled clinical safety andefficacy trials.

Metformin hydrochloride

Metformin may lower serum vitamin B concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on KOMBIGLYZE XR and any apparent abnormalities should be appropriately investigated and managed.[See Warnings and Precautions (5.4) .]

Saxagliptin

Ketoconazole significantly increased saxagliptin exposure. Similar significantincreases in plasma concentrations of saxagliptin are anticipated with otherstrong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole,nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). The doseof saxagliptin should be limited to 2.5 mg when coadministered with a strongCYP3A4/5 inhibitor. [See Dosage and Administration(2.2) and Clinical Pharmacology(12.3) .]

Metformin hydrochloride

Cationicdrugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine,ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminatedby renal tubular secretion theoretically have the potential for interactionwith metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in healthy volunteers. Although such interactionsremain theoretical (except for cimetidine), careful patient monitoring anddose adjustment of KOMBIGLYZE XR and/or the interfering drug is recommended inpatients who are taking cationic medications that are excreted via the proximalrenal tubular secretory system.

Metformin hydrochloride

Some medications can predispose to hyperglycemia and may lead to loss of glycemic control. These medications include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving KOMBIGLYZE XR, the patient should be closely observed for loss of glycemic control. When such drugs are withdrawn from a patient receiving KOMBIGLYZE XR, the patient should be observed closely for hypoglycemia.

There are no adequate and well-controlledstudies in pregnant women with KOMBIGLYZE XR or its individual components. Becauseanimal reproduction studies are not always predictive of human response, KOMBIGLYZE XR,like other antidiabetic medications, should be used during pregnancy onlyif clearly needed.

Coadministration of saxagliptin and metformin, to pregnant rats and rabbits during the period of organogenesis, was neither embryolethal nor teratogenic in either species when tested at doses yielding systemic exposures (AUC) up to 100 and 10 times the maximum recommended human doses (MRHD; saxagliptin 5 mg and metformin 2000 mg), respectively, in rats; and 249 and 1.1 times the MRHDs in rabbits. In rats, minor developmental toxicity was limited to an increased incidence of wavy ribs; associated maternal toxicity was limited to weight decrements of 11% to 17% over the course of the study, and related reductions in maternal food consumption. In rabbits, coadministration was poorly tolerated in a subset of mothers (12 of 30), resulting in death, moribundity, or abortion. However, among surviving mothers with eva luable litters, maternal toxicity was limited to marginal reductions in body weight over the course of gestation days 21 to 29; and associated developmental toxicity in these litters was limited to fetal body weight decrements of 7%, and a low incidence of delayed ossification of the fetal hyoid.

Saxagliptin

Saxagliptinwas not teratogenic at any dose tested when administered to pregnant ratsand rabbits during periods of organogenesis. Incomplete ossification of thepelvis, a form of developmental delay, occurred in rats at a dose of 240 mg/kg,or approximately 1503 and 66 times human exposure to saxagliptin and the activemetabolite, respectively, at the MRHD of5 mg. Maternal toxicity and reduced fetal body weights were observed at 7986and 328 times the human exposure at the MRHD for saxagliptin and the activemetabolite, respectively. Minor skeletal variations in rabbits occurred ata maternally toxic dose of 200 mg/kg, or approximately 1432 and 992 timesthe MRHD.

Saxagliptinadministered to female rats from gestation day 6 to lactation day 20 resultedin decreased body weights in male and female offspring only at maternallytoxic doses (exposures ≥1629 and 53 times saxagliptin and its active metaboliteat the MRHD). No functional or behavioral toxicity was observed in offspringof rats administered saxagliptin at any dose.

Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.

Metformin hydrochloride

Metformin was not teratogenicin rats and rabbits at doses up to 600 mg/kg/day. This represents an exposureof about 2 and 6 times the maximum recommended human daily dose of 2000 mgbased on body surface area comparisons for rats and rabbits, respectively.Determination of fetal concentrations demonstrated a partial placental barrierto metformin.

No studies in lactating animals havebeen conducted with the combined components of KOMBIGLYZE XR. In studiesperformed with the individual components, both saxagliptin and metformin aresecreted in the milk of lactating rats. It is not known whether saxagliptin or metformin are secreted in human milk. Because many drugs are secreted in human milk,caution should be exercised when KOMBIGLYZE XR is administered to a nursing woman.

Safety and effectiveness of KOMBIGLYZE XRin pediatric patients have not been established.

KOMBIGLYZE XR

Elderly patients are more likely to have decreased renal function. Because metformin is contraindicated in patients with renal impairment, carefully monitor renal function in the elderly and use KOMBIGLYZE XR with caution as age increases. [See Warningsand Precautions (5.1,5.2) and Clinical Pharmacology (12.3) .]

Saxagliptin

Inthe six, double-blind, controlled clinical safety and efficacy trials of saxagliptin,634 (15.3%) of the 4148 randomized patients were 65 years and over, and 59(1.4%) patients were 75 years and over. No overall differences in safety oreffectiveness were observed between patients ≥65 years old and the youngerpatients. While this clinical experience has not identified differences inresponses between the elderly and younger patients, greater sensitivity ofsome older individuals cannot be ruled out.

Metformin hydrochloride

Controlled clinical studies ofmetformin did not include sufficient numbers of elderly patients to determinewhether they respond differently from younger patients, although other reportedclinical experience has not identified differences in responses between theelderly and young patients. Metformin is known to be substantially excreted by the kidney. Because the risk of lactic acidosis with metformin is greater in patients with impaired renal function, KOMBIGLYZE XR should only be used in patients withnormal renal function. The initial and maintenance dosing of metformin shouldbe conservative in patients with advanced age due to the potential for decreasedrenal function in this population. Any dose adjustment should be based ona careful assessment of renal function. [See Contraindications(4) , Warnings and Precautions (5.2) , and Clinical Pharmacology (12.3) .]

Saxagliptin

Ina controlled clinical trial, once-daily, orally-administered saxagliptin in healthysubjects at doses up to 400 mg daily for 2 weeks (80 times the MRHD) had nodose-related clinical adverse reactions and no clinically meaningful effecton QTc interval or heart rate.

In the event of an overdose,appropriate supportive treatment should be initiated as dictated by the patient’sclinical status. Saxagliptin and its active metabolite are removed by hemodialysis(23% of dose over 4 hours).

Metformin hydrochloride

Overdose of metformin hydrochloridehas occurred, including ingestion of amounts greater than 50 grams. Hypoglycemiawas reported in approximately 10% of cases, but no causal association withmetformin hydrochloride has been established. Lactic acidosis has been reportedin approximately 32% of metformin overdose cases [see Warningsand Precautions (5.1) ]. Metformin is dialyzable with a clearanceof up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysismay be useful for removal of accumulated drug from patients in whom metforminoverdosage is suspected.

KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release)tablets contain two oral antihyperglycemic medications used in the management oftype 2 diabetes: saxagliptin and metformin hydrochloride.

Saxagliptin

Saxagliptinis an orally-active inhibitor of the dipeptidyl-peptidase-4 (DPP4) enzyme.

Saxagliptinmonohydrate is described chemically as (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3.1.1]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile,monohydrate or (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrate. The empirical formula is CHNO•HO and the molecular weightis 333.43. The structural formula is:

Saxagliptin monohydrateis a white to light yellow or light brown, non-hygroscopic, crystalline powder.It is sparingly soluble in water at 24°C ± 3°C, slightly soluble in ethylacetate, and soluble in methanol, ethanol, isopropyl alcohol, acetonitrile,acetone, and polyethylene glycol 400 (PEG 400).

Metformin hydrochloride

Metformin hydrochloride (N,N-dimethylimidodicarbonimidicdiamide hydrochloride) isa white to off-white crystalline compound with a molecular formula of CHN • HCl and a molecular weight of 165.63. Metformin hydrochloride is freelysoluble in water, slightly soluble in alcohol, and is practically insolublein acetone, ether, and chloroform. The pK of metforminis 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.The structural formula is:

KOMBIGLYZE XR

KOMBIGLYZE XRis available for oral administration as tablets containing either 5.58 mg saxagliptinhydrochloride (anhydrous) equivalent to 5 mg saxagliptin and 500 mg metforminhydrochloride (KOMBIGLYZE XR 5 mg/500 mg), or 5.58 mg saxagliptin hydrochloride(anhydrous) equivalent to 5 mg saxagliptin and 1000 mg metformin hydrochloride(KOMBIGLYZE XR 5 mg/1000 mg), or 2.79 mg saxagliptin hydrochloride (anhydrous)equivalent to 2.5 mg saxagliptin and 1000 mg metformin hydrochloride (KOMBIGLYZE XR2.5 mg/1000 mg). Each film-coated tablet of KOMBIGLYZE XR contains the followinginactive ingredients: carboxymethylcellulose sodium, hypromellose 2208, andmagnesium stearate. The 5 mg/500 mg strength tablet of KOMBIGLYZE XR also containsmicrocrystalline cellulose and hypromellose 2910. In addition, the film coatings contain the following inactive ingredients: polyvinyl alcohol, polyethylene glycol 3350, titanium dioxide, talc, and iron oxides.

Thebiologically inert components of the tablet may occasionally remain intactduring gastrointestinal transit and will be eliminated in the feces as a soft, hydratedmass.

KOMBIGLYZE XR

KOMBIGLYZE XR combines two antihyperglycemic medications with complementary mechanisms of action to improve glycemic control in adults with type 2 diabetes: saxagliptin, a dipeptidyl-peptidase-4 (DPP4) inhibitor, and metformin hydrochloride, a biguanide.

Saxagliptin

Increased concentrations of the incretin hormones such as glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are releasedinto the bloodstream from the small intestine in response to meals. Thesehormones cause insulin release from the pancreatic beta cells in a glucose-dependentmanner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowersglucagon secretion from pancreatic alpha cells, reducing hepatic glucose production.In patients with type 2 diabetes, concentrations of GLP-1 are reduced butthe insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP4inhibitor that slows the inactivation of the incretin hormones, thereby increasingtheir bloodstream concentrations and reducing fasting and postprandial glucoseconcentrations in a glucose-dependent manner in patients with type 2 diabetesmellitus.

Metformin hydrochloride

Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in unusual circumstances [see Warnings and Precautions (5.8) ]and does not cause hyperinsulinemia. With metformin therapy, insulin secretionremains unchanged while fasting insulin levels and day-long plasma insulinresponse may actually decrease.

Saxagliptin

In patients with type 2 diabetes mellitus, administration of saxagliptininhibits DPP4 enzyme activity for a 24-hour period. After an oral glucoseload or a meal, this DPP4 inhibition resulted in a 2- to 3-fold increase incirculating levels of active GLP-1 and GIP, decreased glucagon concentrations,and increased glucose-dependent insulin secretion from pancreatic beta cells.The rise in insulin and decrease in glucagon were associated with lower fastingglucose concentrations and reduced glucose excursion following an oral glucoseload or a meal.

Saxagliptin

In a randomized, double-blind, placebo-controlled, 4-way crossover, activecomparator study using moxifloxacin in 40 healthy subjects, saxagliptin wasnot associated with clinically meaningful prolongation of the QTc intervalor heart rate at daily doses up to 40 mg (8 times the MRHD).

KOMBIGLYZE XR

Bioequivalence and food effect of KOMBIGLYZE XR was characterized under low calorie diet. The low calorie diet consisted of 324 kcal with meal composition that contained 11.1% protein, 10.5% fat, and 78.4% carbohydrate. The results of bioequivalence studies in healthy subjects demonstrated that KOMBIGLYZE XR combination tablets are bioequivalent to coadministration of corresponding doses of saxagliptin (ONGLYZA™) and metformin hydrochloride extended-release (GLUCOPHAGE XR) as individual tablets under fed conditions.

Saxagliptin

Thepharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptinwere similar in healthy subjects and in patients with type 2 diabetes mellitus.The C and AUC values of saxagliptin and its activemetabolite increased proportionally in the 2.5 to 400 mg dose range. Followinga 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasmaAUC values for saxagliptin and its active metabolite were 78 ng•h/mL and 214ng•h/mL, respectively. The corresponding plasma C values were 24 ng/mLand 47 ng/mL, respectively. The average variability (%CV) for AUC and C for both saxagliptin and its active metabolite was less than 25%.

Noappreciable accumulation of either saxagliptin or its active metabolite wasobserved with repeated once-daily dosing at any dose level. No dose- and time-dependencewere observed in the clearance of saxagliptin and its active metabolite over14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to400 mg.

Metformin hydrochloride

Metformin extended-release C is achieved with a median value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and C are less than dose proportional for metformin extended-release within the range of 500 to 2000 mg. After repeated administration of metformin extended-release, metformin did not accumulate in plasma. Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism. Peak plasma levels of metformin extended-release tablets are approximately 20% lower compared to the same dose of metformin immediate-release tablets, however, the extent of absorption (as measured by AUC) is similar between extended-release tablets and immediate-release tablets.

Saxagliptin

The median time to maximum concentration (T) followingthe 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its activemetabolite. Administration with a high-fat meal resulted in an increase inT of saxagliptin by approximately 20 minutes ascompared to fasted conditions. There was a 27% increase in the AUC of saxagliptinwhen given with a meal as compared to fasted conditions. Saxagliptin may beadministered with or without food. Food has no significant effect on the pharmacokinetics of saxagliptin when administered as KOMBIGLYZE XR combination tablets.

Metformin hydrochloride

Following a single oral dose of metformin extended-release, C is achieved with a median value of 7 hours and a range of 4 to 8 hours. Although the extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food, there was no effect of food on C and T of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin extended-release. Food has no significant effect on the pharmacokinetics of metformin when administered as KOMBIGLYZE XR combination tablets.

Saxagliptin

The in vitro protein binding of saxagliptin and its activemetabolite in human serum is negligible. Therefore, changes in blood proteinlevels in various disease states (e.g., renal or hepatic impairment) are notexpected to alter the disposition of saxagliptin.

Metformin hydrochloride

Distribution studies with extended-releasemetformin have not been conducted; however, the apparent volume of distribution(V/F) of metformin following single oral doses of immediate-release metformin850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins,in contrast to sulfonylureas, which are more than 90% protein bound. Metforminpartitions into erythrocytes, most likely as a function of time. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

Saxagliptin

The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5(CYP3A4/5). The major metabolite of saxagliptin is also a DPP4 inhibitor,which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitorsand inducers will alter the pharmacokinetics of saxagliptin and its activemetabolite. [See Drug Interactions (7.1) .]

Metformin hydrochloride

Intravenous single-dose studiesin healthy subjects demonstrate that metformin is excreted unchanged in theurine and does not undergo hepatic metabolism (no metabolites have been identifiedin humans) or biliary excretion.

Metabolism studieswith extended-release metformin tablets have not been conducted.

Saxagliptin

Saxagliptin is eliminated by both renal and hepatic pathways. Following asingle 50 mg dose of C-saxagliptin, 24%, 36%,and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite,and total radioactivity, respectively. The average renal clearance of saxagliptin(~230 mL/min) was greater than the average estimated glomerular filtrationrate (~120 mL/min), suggesting some active renal excretion. A total of 22%of the administered radioactivity was recovered in feces representing thefraction of the saxagliptin dose excreted in bile and/or unabsorbed drug fromthe gastrointestinal tract. Following a single oral dose of saxagliptin 5mg to healthy subjects, the mean plasma terminal half-life (t)for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.

Metformin hydrochloride

Renal clearance is approximately3.5 times greater than creatinine clearance, which indicates that tubularsecretion is the major route of metformin elimination. Following oral administration,approximately 90% of the absorbed drug is eliminated via the renal route withinthe first 24 hours, with a plasma elimination half-life of approximately 6.2hours. In blood, the elimination half-life is approximately 17.6 hours, suggestingthat the erythrocyte mass may be a compartment of distribution.

KOMBIGLYZE XR

In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance. Use of metformin in patients with renal impairment increases the risk for lactic acidosis. Because KOMBIGLYZE XR contains metformin, KOMBIGLYZE XR is contraindicated in patients with renal impairment [see Contraindications (4) and Warningsand Precautions (5.2) ].

No pharmacokinetic studies ofmetformin have been conducted in patients with hepatic impairment. Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Because KOMBIGLYZE XR contains metformin, KOMBIGLYZE XR is not recommended in patients with hepatic impairment [see Warningsand Precautions (5.3) ].

Saxagliptin

No dosage adjustment is recommended based on body mass index (BMI) whichwas not identified as a significant covariate on the apparent clearance ofsaxagliptin or its active metabolite in the population pharmacokinetic analysis.

Saxagliptin

No dosage adjustment is recommended based on gender. There were no differencesobserved in saxagliptin pharmacokinetics between males and females. Comparedto males, females had approximately 25% higher exposure values for the activemetabolite than males, but this difference is unlikely to be of clinical relevance.Gender was not identified as a significant covariate on the apparent clearanceof saxagliptin and its active metabolite in the population pharmacokineticanalysis.

Metformin hydrochloride

Metformin pharmacokinetic parametersdid not differ significantly between healthy subjects and patients with type2 diabetes when analyzed according to gender (males=19, females=16). Similarly,in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemiceffect of metformin was comparable in males and females.

Saxagliptin

No dosage adjustment is recommended based on age alone. Elderly subjects(65-80 years of age) had 23% and 59% higher geometric mean C andgeometric mean AUC values, respectively, for saxagliptin than young subjects(18-40 years of age). Differences in active metabolite pharmacokinetics between elderlyand young subjects generally reflected the differences observed in saxagliptinpharmacokinetics. The difference between the pharmacokinetics of saxagliptinand the active metabolite in young and elderly subjects is likely due to multiplefactors including declining renal function and metabolic capacity with increasingage. Age was not identified as a significant covariate on the apparent clearanceof saxagliptin and its active metabolite in the population pharmacokineticanalysis.

Metformin hydrochloride

Limited data from controlledpharmacokinetic studies of metformin in healthy elderly subjects suggest thattotal plasma clearance of metformin is decreased, the half-life is prolonged,and C is increased, compared to healthy young subjects.From these data, it appears that the change in metformin pharmacokineticswith aging is primarily accounted for by a change in renal function.

KOMBIGLYZE XRshould not be initiated in patients of any age unless measurement ofcreatinine clearance demonstrates that renal function is normal [see Warnings and Precautions (5.1, 5.2) ].

Safety and effectiveness of KOMBIGLYZE XR in pediatric patients have not been established.

Saxagliptin

No dosage adjustment is recommended based on race. The population pharmacokineticanalysis compared the pharmacokinetics of saxagliptin and its active metabolitein 309 Caucasian subjects with 105 non-Caucasian subjects (consisting of sixracial groups). No significant difference in the pharmacokinetics of saxagliptinand its active metabolite were detected between these two populations.

Metformin hydrochloride

No studies of metformin pharmacokineticparameters according to race have been performed. In controlled clinical studiesof metformin in patients with type 2 diabetes, the antihyperglycemic effectwas comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Specificpharmacokinetic drug interaction studies with KOMBIGLYZE XR have not been performed,although such studies have been conducted with the individual saxagliptinand metformin components.

In invitro studies, saxagliptin and its active metabolite did not inhibitCYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9,or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearanceof coadministered drugs that are metabolized by these enzymes. Saxagliptinis a P-glycoprotein (P-gp) substrate, but is not a significant inhibitor orinducer of P-gp.

Manufacturer

E.R. Squibb & Sons, L.L.C.

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
•  Last Updated: 2nd of March 2011