Kombiglyze xr (metformin hydrochloride_saxagliptin)

Overdose

In a controlled clinical trial, once-daily, orally administered saxagliptin in healthy subjects at doses up to 400 mg daily for 2 weeks (80 times the MRHD) had no dose-related clinical adverse reactions and no clinically meaningful effect on QTc interval or heart rate.

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

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Contraindications

KOMBIGLYZE XR is contraindicated in patients with:

• Renal impairment (e.g., serum creatinine levels ≥ 1.5 mg/dL for men, ≥ 1.4 mg/dL for women, or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
• Hypersensitivity to metformin hydrochloride.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.
• History of a serious hypersensitivity reaction to KOMBIGLYZE XR or saxagliptin, such as anaphylaxis, angioedema, or exfoliative skin conditions.

Undesirable effects

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.

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.

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. The 10 mg saxagliptin dosage is not an approved dosage.

In a pre-specified pooled analysis of the 24-week data (regardless of glycemic rescue) from the two monotherapy trials, the add-on to metformin immediate-release trial, the add-on to thiazolidinedione (TZD) trial, and the add-on to glyburide trial, the overall incidence of adverse events in patients treated with saxagliptin 2.5 mg and saxagliptin 5 mg was similar to placebo (72% and 72.2% versus 70.6%, respectively). Discontinuation of therapy due to adverse events occurred in 2.2%, 3.3%, and 1.8% of patients receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. The most common adverse events (reported in at least 2 patients treated with saxagliptin 2.5 mg or at least 2 patients treated with saxagliptin 5 mg) associated with premature discontinuation of therapy 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% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). The adverse reactions in this pooled analysis reported (regardless of investigator assessment of causality) in ≥ 5% of patients treated with saxagliptin 5 mg, and more commonly than in patients treated with placebo are shown in Table 1.

Table 1: Adverse Reactions in Placebo-Controlled Trials* Reported in ≥ 5% of Patients Treated with Saxagliptin 5 mg and More Commonly than in Patients Treated with Placebo

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

In this pooled analysis, adverse reactions that were reported in ≥ 2% of patients treated with saxagliptin 2.5 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 of fractures 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 10 mg saxagliptin dosage is not an approved dosage. The incidence rate of fracture events in patients who received saxagliptin did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of saxagliptin on bone.

An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to saxagliptin is not known.

In the add-on to insulin trial , the incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between saxagliptin and placebo, except for confirmed hypoglycemia.

Table 2 shows the adverse reactions reported (regardless of investigator assessment of causality) in ≥ 5% of patients participating in an additional 24-week, active-controlled trial of coadministered saxagliptin and metformin in treatment-naive patients.

Table 2: Coadministration of Saxagliptin and Metformin Immediate-Release in Treatment-Naive Patients: Adverse Reactions Reported in ≥ 5% of Patients Treated with Combination Therapy of Saxagliptin 5 mg Plus Metformin Immediate-Release (and More Commonly than in Patients Treated with Metformin Immediate-Release Alone)

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 or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia.

The incidence of reported hypoglycemia for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo given as monotherapy was 4% 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% 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% in patients given placebo + metformin immediate-release.

In the active-controlled trial comparing add-on therapy with saxagliptin 5 mg to glipizide in patients inadequately controlled on metformin alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with saxagliptin 5 mg versus 36.3% (750 events in 156 patients) with glipizide. Confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤ 50 mg/dL) was reported in none of the saxagliptin-treated patients and in 35 glipizide-treated patients (8.1%) (p < 0.0001).

In the saxagliptin add-on to insulin trial, the overall incidence of reported hypoglycemia was 18.4% for saxagliptin 5 mg and 19.9% for placebo. However, the incidence of confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤ 50 mg/dL) was higher with saxagliptin 5 mg (5.3%) versus placebo (3.3%). Among the patients using insulin in combination with metformin, the incidence of confirmed symptomatic hypoglycemia was 4.8% with saxagliptin versus 1.9% with placebo.

In the saxagliptin add-on to metformin plus sulfonylurea trial, the overall incidence of reported hypoglycemia was 10.1% for saxagliptin 5 mg and 6.3% for placebo. Confirmed hypoglycemia was reported in 1.6% of the saxagliptin-treated patients and in none of the placebo-treated patients.

Saxagliptin

Hypersensitivity-related events, such as urticaria and facial edema in the 5-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 required hospitalization or were reported as life-threatening by the investigators. One saxagliptin-treated patient in this pooled analysis discontinued due to generalized 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 patients treated with saxagliptin alone or in combination with metformin.

Saxagliptin

There was a dose-related mean decrease in absolute lymphocyte count observed with saxagliptin. From a baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with saxagliptin 5 mg and 10 mg, respectively, relative to placebo were observed at 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 observed for saxagliptin 2.5 mg relative to placebo. The proportion of patients who were 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 repeated exposure to saxagliptin although some patients had recurrent decreases upon rechallenge that led to discontinuation of saxagliptin. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The 10 mg saxagliptin dosage is not an approved dosage.

The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.

Metformin Hydrochloride

Metformin may lower serum vitamin B12 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.

Additional adverse reactions have been identified during postapproval use of saxagliptin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions.
• Acute pancreatitis.
• Severe and disabling arthralgia.

Therapeutic indications

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.

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

KOMBIGLYZE XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using KOMBIGLYZE XR.

Pharmacodynamic properties

In patients with type 2 diabetes mellitus, administration of saxagliptin inhibits DPP4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP4 inhibition resulted in a 2- to 3-fold increase in circulating 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 fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study using moxifloxacin in 40 healthy subjects, saxagliptin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8 times the MRHD).

Pharmacokinetic properties

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.

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

No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg.

Metformin extended-release Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and Cmax 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 (Tmax) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite. Administration with a high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. Saxagliptin may be administered 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, Cmax 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 Cmax and Tmax 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 active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.

Metformin Hydrochloride

Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions 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 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite.

Metformin Hydrochloride

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

Metabolism studies with extended-release metformin tablets have not been conducted.

Saxagliptin

Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-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 filtration rate (~120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following a single oral dose of saxagliptin 5 mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.

Metformin Hydrochloride

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

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Fertility, pregnancy and lactation

There are no adequate and well-controlled studies in pregnant women with KOMBIGLYZE XR or its individual components. Because animal reproduction studies are not always predictive of human response, KOMBIGLYZE XR, like other antidiabetic medications, should be used during pregnancy only if 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 evaluable 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 was not teratogenic at any dose tested when administered to pregnant rats and rabbits during periods of organogenesis. Incomplete ossification of the pelvis, 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 active metabolite, respectively, at the MRHD of 5 mg. Maternal toxicity and reduced fetal body weights were observed at 7986 and 328 times the human exposure at the MRHD for saxagliptin and the active metabolite, respectively. Minor skeletal variations in rabbits occurred at a maternally toxic dose of 200 mg/kg, or approximately 1432 and 992 times the MRHD.

Saxagliptin administered to female rats from gestation day 6 to lactation day 20 resulted in decreased body weights in male and female offspring only at maternally toxic doses (exposures ≥ 1629 and 53 times saxagliptin and its active metabolite at the MRHD). No functional or behavioral toxicity was observed in offspring of rats administered saxagliptin at any dose.

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

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

Qualitative and quantitative composition

• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) 5 mg/500 mg tablets are light brown to brown, biconvex, capsule-shaped, film-coated tablets with “5/500” printed on one side and “4221” printed on the reverse side, in blue ink.
• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) 5 mg/1000 mg tablets are pink, biconvex, capsule-shaped, film-coated tablets with “5/1000” printed on one side and “4223” printed on the reverse side, in blue ink.
• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) 2.5 mg/1000 mg tablets are pale yellow to light yellow, biconvex, capsule-shaped, film-coated tablets with “2.5/1000” printed on one side and “4222” printed on the reverse side, in blue ink.

KOMBIGLYZE® XR (saxagliptin and metformin HCl extended-release) tablets have markings on both sides and are available in the strengths and packages listed in Table 12

Table 12: KOMBIGLYZE XR Tablet Presentations

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. Revised: August 2015

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment 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 pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels ( > 5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/ pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 μg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake when taking metformin since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin 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 only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal, but less than 5 mmol/L, in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling .

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.

There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin. After initiation of KOMBIGLYZE XR, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, KOMBIGLYZE XR should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using KOMBIGLYZE XR.

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.

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 B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 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.

Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 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 evaluated 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 evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation 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.

When saxagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with KOMBIGLYZE XR.

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 , 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. 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-evaluated 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 postmarketing reports of serious hypersensitivity reactions in patients treated with saxagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue KOMBIGLYZE XR, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with KOMBIGLYZE XR.

There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP4 inhibitor. Consider DPP4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

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

See FDA-approved patient labeling (Medication Guide).

Healthcare providers should instruct their patients to read the Medication Guide before starting KOMBIGLYZE XR therapy and to reread it each time the prescription is renewed. Patients should be instructed to inform their healthcare provider if they develop any unusual symptom or if any existing symptom persists or worsens.

Patients should be informed of the potential risks and benefits of KOMBIGLYZE XR and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly.

The risks of lactic acidosis due to the metformin component, its symptoms and conditions that predispose to its development, as noted in Warnings and Precautions (5.1), should be explained to patients. Patients should be advised to discontinue KOMBIGLYZE XR immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heartbeat, sensation of feeling cold (especially in the extremities), or other nonspecific symptoms occur. Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of KOMBIGLYZE XR therapy; however, patients should consult their physician if they develop unexplained symptoms. Although gastrointestinal symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious disease.

Patients should be counseled against excessive alcohol intake while receiving KOMBIGLYZE XR.

Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with KOMBIGLYZE XR.

Patients should be informed that acute pancreatitis has been reported during postmarketing use of saxagliptin. Before initiating KOMBIGLYZE XR, patients should be questioned about other risk factors for pancreatitis, such as a history of pancreatitis, alcoholism, gallstones, or hypertriglyceridemia. Patients should also be informed that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue KOMBIGLYZE XR and contact their physician if persistent severe abdominal pain occurs.

Patients should be informed that the incidence of hypoglycemia may be increased when KOMBIGLYZE XR is added to an insulin secretagogue (e.g., sulfonylurea) or insulin.

Patients should be informed that serious allergic (hypersensitivity) reactions, such as angioedema, anaphylaxis, and exfoliative skin conditions, have been reported during postmarketing use of saxagliptin. If symptoms of these allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking KOMBIGLYZE XR and seek medical advice promptly.

Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs.

Patients should be informed that KOMBIGLYZE XR must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

Patients should be informed that if they miss a dose of KOMBIGLYZE XR, they should take the next dose as prescribed, unless otherwise instructed by their healthcare provider. Patients should be instructed not to take an extra dose the next day.

KOMBIGLYZE XR

No animal studies have been conducted with KOMBIGLYZE XR to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on the findings in the studies with saxagliptin and metformin individually.

Saxagliptin

Saxagliptin did not induce tumors in either mice (50, 250, and 600 mg/kg) or rats (25, 75, 150, and 300 mg/kg) at the highest doses evaluated. The highest doses evaluated in mice were equivalent to approximately 870 (males) and 1165 (females) times the human exposure at the MRHD of 5 mg/day. In rats, exposures were approximately 355 (males) and 2217 (females) times the MRHD.

Metformin Hydrochloride

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

Saxagliptin

Saxagliptin was not mutagenic or clastogenic with or without metabolic activation in an in vitro Ames bacterial assay, an in vitro cytogenetics assay in primary human lymphocytes, an in vivo oral micronucleus assay in rats, an in vivo oral DNA repair study in rats, and an oral in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes. The active metabolite was not mutagenic in an in vitro Ames bacterial assay.

Metformin Hydrochloride

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Saxagliptin

In a rat fertility study, males were treated with oral gavage doses for 2 weeks prior to mating, during mating, and up to scheduled termination (approximately 4 weeks total) and females were treated with oral gavage doses for 2 weeks prior to mating through gestation day 7. No adverse effects on fertility were observed at exposures of approximately 603 (males) and 776 (females) times the MRHD. Higher doses that elicited maternal toxicity also increased fetal resorptions (approximately 2069 and 6138 times the MRHD). Additional effects on estrous cycling, fertility, ovulation, and implantation were observed at approximately 6138 times the MRHD.

Metformin Hydrochloride

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.

There are no adequate and well-controlled studies in pregnant women with KOMBIGLYZE XR or its individual components. Because animal reproduction studies are not always predictive of human response, KOMBIGLYZE XR, like other antidiabetic medications, should be used during pregnancy only if 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 evaluable 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 was not teratogenic at any dose tested when administered to pregnant rats and rabbits during periods of organogenesis. Incomplete ossification of the pelvis, 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 active metabolite, respectively, at the MRHD of 5 mg. Maternal toxicity and reduced fetal body weights were observed at 7986 and 328 times the human exposure at the MRHD for saxagliptin and the active metabolite, respectively. Minor skeletal variations in rabbits occurred at a maternally toxic dose of 200 mg/kg, or approximately 1432 and 992 times the MRHD.

Saxagliptin administered to female rats from gestation day 6 to lactation day 20 resulted in decreased body weights in male and female offspring only at maternally toxic doses (exposures ≥ 1629 and 53 times saxagliptin and its active metabolite at the MRHD). No functional or behavioral toxicity was observed in offspring of rats administered saxagliptin at any dose.

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

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

No studies in lactating animals have been conducted with the combined components of KOMBIGLYZE XR. In studies performed with the individual components, both saxagliptin and metformin are secreted 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 XR in pediatric patients under 18 years of age have not been established. Additionally, studies characterizing the pharmacokinetics of KOMBIGLYZE XR in pediatric patients have not been performed.

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.

In the 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 or effectiveness were observed between patients ≥ 65 years old and the younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly 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 with normal renal function. The 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. Any dose adjustment should be based on a careful assessment of renal function.

Dosage (Posology) and method of administration

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:

• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets 5 mg/500 mg
• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets 5 mg/1000 mg
• KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets 2.5 mg/1000 mg

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 dosage 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 dosage 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 XR in patients previously treated with other antihyperglycemic medications and switched to KOMBIGLYZE XR. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Inform patients that KOMBIGLYZE XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of KOMBIGLYZE XR will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet

The maximum recommended dosage 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 dosage to 2.5 mg/1000 mg once daily.

When KOMBIGLYZE XR is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dosage of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia.

Interaction with other medicinal products and other forms of interaction

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.

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.

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. The 10 mg saxagliptin dosage is not an approved dosage.

In a pre-specified pooled analysis of the 24-week data (regardless of glycemic rescue) from the two monotherapy trials, the add-on to metformin immediate-release trial, the add-on to thiazolidinedione (TZD) trial, and the add-on to glyburide trial, the overall incidence of adverse events in patients treated with saxagliptin 2.5 mg and saxagliptin 5 mg was similar to placebo (72% and 72.2% versus 70.6%, respectively). Discontinuation of therapy due to adverse events occurred in 2.2%, 3.3%, and 1.8% of patients receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. The most common adverse events (reported in at least 2 patients treated with saxagliptin 2.5 mg or at least 2 patients treated with saxagliptin 5 mg) associated with premature discontinuation of therapy 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% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). The adverse reactions in this pooled analysis reported (regardless of investigator assessment of causality) in ≥ 5% of patients treated with saxagliptin 5 mg, and more commonly than in patients treated with placebo are shown in Table 1.

Table 1: Adverse Reactions in Placebo-Controlled Trials* Reported in ≥ 5% of Patients Treated with Saxagliptin 5 mg and More Commonly than in Patients Treated with Placebo

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

In this pooled analysis, adverse reactions that were reported in ≥ 2% of patients treated with saxagliptin 2.5 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 of fractures 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 10 mg saxagliptin dosage is not an approved dosage. The incidence rate of fracture events in patients who received saxagliptin did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of saxagliptin on bone.

An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to saxagliptin is not known.

In the add-on to insulin trial , the incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between saxagliptin and placebo, except for confirmed hypoglycemia.

Table 2 shows the adverse reactions reported (regardless of investigator assessment of causality) in ≥ 5% of patients participating in an additional 24-week, active-controlled trial of coadministered saxagliptin and metformin in treatment-naive patients.

Table 2: Coadministration of Saxagliptin and Metformin Immediate-Release in Treatment-Naive Patients: Adverse Reactions Reported in ≥ 5% of Patients Treated with Combination Therapy of Saxagliptin 5 mg Plus Metformin Immediate-Release (and More Commonly than in Patients Treated with Metformin Immediate-Release Alone)

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 or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia.

The incidence of reported hypoglycemia for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo given as monotherapy was 4% 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% 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% in patients given placebo + metformin immediate-release.

In the active-controlled trial comparing add-on therapy with saxagliptin 5 mg to glipizide in patients inadequately controlled on metformin alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with saxagliptin 5 mg versus 36.3% (750 events in 156 patients) with glipizide. Confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤ 50 mg/dL) was reported in none of the saxagliptin-treated patients and in 35 glipizide-treated patients (8.1%) (p < 0.0001).

In the saxagliptin add-on to insulin trial, the overall incidence of reported hypoglycemia was 18.4% for saxagliptin 5 mg and 19.9% for placebo. However, the incidence of confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤ 50 mg/dL) was higher with saxagliptin 5 mg (5.3%) versus placebo (3.3%). Among the patients using insulin in combination with metformin, the incidence of confirmed symptomatic hypoglycemia was 4.8% with saxagliptin versus 1.9% with placebo.

In the saxagliptin add-on to metformin plus sulfonylurea trial, the overall incidence of reported hypoglycemia was 10.1% for saxagliptin 5 mg and 6.3% for placebo. Confirmed hypoglycemia was reported in 1.6% of the saxagliptin-treated patients and in none of the placebo-treated patients.

Saxagliptin

Hypersensitivity-related events, such as urticaria and facial edema in the 5-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 required hospitalization or were reported as life-threatening by the investigators. One saxagliptin-treated patient in this pooled analysis discontinued due to generalized 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 patients treated with saxagliptin alone or in combination with metformin.

Saxagliptin

There was a dose-related mean decrease in absolute lymphocyte count observed with saxagliptin. From a baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with saxagliptin 5 mg and 10 mg, respectively, relative to placebo were observed at 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 observed for saxagliptin 2.5 mg relative to placebo. The proportion of patients who were 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 repeated exposure to saxagliptin although some patients had recurrent decreases upon rechallenge that led to discontinuation of saxagliptin. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The 10 mg saxagliptin dosage is not an approved dosage.

The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.

Metformin Hydrochloride

Metformin may lower serum vitamin B12 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.

Additional adverse reactions have been identified during postapproval use of saxagliptin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions.
• Acute pancreatitis.
• Severe and disabling arthralgia.

Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). The dose of saxagliptin should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor.

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

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.