Kombiglyze XR 2.5mg/1000mg

Kombiglyze XR 2.5mg/1000mg 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 (Kombiglyze XR 2.5mg/1000mg) and Metformin (Kombiglyze XR 2.5mg/1000mg) is appropriate.

Important Limitations of Use: Kombiglyze XR 2.5mg/1000mg should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. Kombiglyze XR 2.5mg/1000mg 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 2.5mg/1000mg.

Kombiglyze XR 2.5mg/1000mg are oral diabetes medicines that help control blood sugar levels. Metformin (Kombiglyze XR 2.5mg/1000mg) works by decreasing glucose (sugar) production in the liver and decreasing absorption of glucose by the intestines. Saxagliptin (Kombiglyze XR 2.5mg/1000mg) works by regulating the levels of insulin your body produces after eating.

The combination of Kombiglyze XR 2.5mg/1000mg is used to treat type 2 diabetes. This medication is not for treating type 1 diabetes.

Kombiglyze XR 2.5mg/1000mg may also be used for purposes not listed in this medication guide.

Recommended

Dosage:

If therapy with a combination tablet containing Saxagliptin (Kombiglyze XR 2.5mg/1000mg) and Metformin (Kombiglyze XR 2.5mg/1000mg) is considered appropriate, the recommended dose of Saxagliptin (Kombiglyze XR 2.5mg/1000mg) is 5 mg once daily. The recommended starting dose of Metformin (Kombiglyze XR 2.5mg/1000mg) extended-release is 500 mg once daily, which can be titrated to 2,000 mg once daily. The maximum dose of Saxagliptin (Kombiglyze XR 2.5mg/1000mg)/Metformin (Kombiglyze XR 2.5mg/1000mg) HCl (Kombiglyze XR 2.5mg/1000mg) is Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg/Metformin (Kombiglyze XR 2.5mg/1000mg) extended-release 2,000 mg taken as two 2.5 mg/1,000 mg tablets once daily.

No studies have been performed specifically examining the safety and efficacy of Saxagliptin (Kombiglyze XR 2.5mg/1000mg)/Metformin (Kombiglyze XR 2.5mg/1000mg) HCl (Kombiglyze XR 2.5mg/1000mg) in patients previously treated with other antihyperglycemic agents and switched to Saxagliptin (Kombiglyze XR 2.5mg/1000mg)/Metformin (Kombiglyze XR 2.5mg/1000mg) HCl (Kombiglyze XR 2.5mg/1000mg). Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Patients should be informed that Saxagliptin (Kombiglyze XR 2.5mg/1000mg)/Metformin (Kombiglyze XR 2.5mg/1000mg) HCl (Kombiglyze XR 2.5mg/1000mg) tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of Saxagliptin (Kombiglyze XR 2.5mg/1000mg)/Metformin (Kombiglyze XR 2.5mg/1000mg) HCl (Kombiglyze XR 2.5mg/1000mg) will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet.

Special Populations: Patients with Renal Impairment: Saxagliptin (Kombiglyze XR 2.5mg/1000mg)/Metformin (Kombiglyze XR 2.5mg/1000mg) HCl (Kombiglyze XR 2.5mg/1000mg) is contraindicated in patients with renal impairment.

Patients with Hepatic Impairment: Since impaired hepatic function has been associated with some cases of lactic acidosis in patients taking Metformin (Kombiglyze XR 2.5mg/1000mg), Saxagliptin (Kombiglyze XR 2.5mg/1000mg)/Metformin (Kombiglyze XR 2.5mg/1000mg) HCl (Kombiglyze XR 2.5mg/1000mg) should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment.

Pediatric and Adolescent Patients: Safety and effectiveness of Saxagliptin (Kombiglyze XR 2.5mg/1000mg)/Metformin (Kombiglyze XR 2.5mg/1000mg) HCl (Kombiglyze XR 2.5mg/1000mg) in pediatric and adolescent patients have not been established.

Geriatric Patients: Because Saxagliptin (Kombiglyze XR 2.5mg/1000mg) and Metformin (Kombiglyze XR 2.5mg/1000mg) are eliminated in part by the kidney, and because elderly patients are more likely to have decreased renal function, Saxagliptin (Kombiglyze XR 2.5mg/1000mg)/Metformin (Kombiglyze XR 2.5mg/1000mg) HCl (Kombiglyze XR 2.5mg/1000mg) should be used with caution as age increases.

See also:
What is the most important information I should know about Kombiglyze XR 2.5mg/1000mg?

Kombiglyze XR 2.5mg/1000mg 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 (Kombiglyze XR 2.5mg/1000mg) 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 2.5mg/1000mg or Saxagliptin (Kombiglyze XR 2.5mg/1000mg), such as anaphylaxis, angioedema, or exfoliative skin conditions.

Kombiglyze XR 2.5mg/1000mg should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials because use of such products may result in acute alteration of renal function.

Use Kombiglyze XR 2.5mg/1000mg as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Kombiglyze XR 2.5mg/1000mg comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Kombiglyze XR 2.5mg/1000mg refilled.
• Take Kombiglyze XR 2.5mg/1000mg by mouth with the evening meal unless your doctor tells you otherwise.
• Swallow Kombiglyze XR 2.5mg/1000mg whole. Do not break, crush, or chew before swallowing.
• Take Kombiglyze XR 2.5mg/1000mg on a regular schedule to get the most benefit from it. Taking Kombiglyze XR 2.5mg/1000mg at the same time each day will help you remember to take it.
• Continue to take Kombiglyze XR 2.5mg/1000mg even if you feel well. Do not miss any doses.
• If you miss a dose of Kombiglyze XR 2.5mg/1000mg, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Kombiglyze XR 2.5mg/1000mg.

Use: Labeled Indications

Diabetes mellitus, type 2: Management of adults with type 2 diabetes mellitus as an adjunct to diet and exercise when treatment with both Saxagliptin (Kombiglyze XR 2.5mg/1000mg) and Metformin (Kombiglyze XR 2.5mg/1000mg) is appropriate.

See also:
What other drugs will affect Kombiglyze XR 2.5mg/1000mg?

Strong Inhibitors of CYP3A4/5 Enzymes: Saxagliptin (Kombiglyze XR 2.5mg/1000mg): Ketoconazole significantly increased Saxagliptin (Kombiglyze XR 2.5mg/1000mg) exposure. Similar significant increases in plasma concentrations of Saxagliptin (Kombiglyze XR 2.5mg/1000mg) are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). The dose of Saxagliptin (Kombiglyze XR 2.5mg/1000mg) should be limited to 2.5 mg when co-administered with a strong CYP3A4/5 inhibitor.

Cationic Drugs: Metformin (Kombiglyze XR 2.5mg/1000mg) Hydrochloride: 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 (Kombiglyze XR 2.5mg/1000mg) by competing for common renal tubular transport systems. Such interaction between Metformin (Kombiglyze XR 2.5mg/1000mg) 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 2.5mg/1000mg and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Use with Other Drugs: Metformin (Kombiglyze XR 2.5mg/1000mg) 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 2.5mg/1000mg, the patient should be closely observed for loss of glycemic control. When such drugs are withdrawn from a patient receiving Kombiglyze XR 2.5mg/1000mg, the patient should be observed closely for hypoglycemia.

See also:
What are the possible side effects of Kombiglyze XR 2.5mg/1000mg?

Clinical Trials Experience: 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.

Monotherapy and Add-On Combination Therapy: Metformin (Kombiglyze XR 2.5mg/1000mg) Hydrochloride: In placebo-controlled monotherapy trials of Metformin (Kombiglyze XR 2.5mg/1000mg) extended-release, diarrhea and nausea/vomiting were reported in >5% of Metformin (Kombiglyze XR 2.5mg/1000mg)-treated patients and more commonly than in placebo-treated patients (9.6% vs 2.6% for diarrhea and 6.5% vs 1.5% for nausea/vomiting). Diarrhea led to discontinuation of study medication in 0.6% of the patients treated with Metformin (Kombiglyze XR 2.5mg/1000mg) extended-release.

Saxagliptin (Kombiglyze XR 2.5mg/1000mg): In 2 placebo-controlled monotherapy trials of 24-week duration, patients were treated with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 2.5 mg daily, Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg daily, and placebo. Three 24-week, placebo-controlled, add-on combination therapy trials were also conducted: One with Metformin (Kombiglyze XR 2.5mg/1000mg) immediate-release, 1 with a thiazolidinedione (pioglitazone or rosiglitazone), and 1 with glyburide. In these 3 trials, patients were randomized to add-on therapy with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 2.5 mg daily, Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg daily, or placebo. A Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 10-mg treatment arm was included in 1 of the monotherapy trials and in the add-on combination trial with Metformin (Kombiglyze XR 2.5mg/1000mg) immediate-release.

In a prespecified pooled analysis of the 24-week data (regardless of glycemic rescue) from the 2 monotherapy trials, the add-on to Metformin (Kombiglyze XR 2.5mg/1000mg) 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 (Kombiglyze XR 2.5mg/1000mg) 2.5 mg and Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg was similar to placebo (72% and 72.2% vs 70.6%, respectively). Discontinuation of therapy due to adverse events occurred in 2.2%, 3.3%, and 1.8% of patients receiving Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 2.5 mg, Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg, and placebo, respectively. The most common adverse events (reported in at least 2 patients treated with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 2.5 mg or at least 2 patients treated with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg) associated with premature discontinuation of therapy included lymphopenia (0.1% and 0.5% vs 0%, respectively), rash (0.2% and 0.3% vs 0.3%), increased blood creatinine (0.3% and 0% vs 0%), and increased blood creatine phosphokinase (0.1% and 0.2% vs 0%). The adverse reactions in this pooled analysis reported (regardless of investigator assessment of causality) in ≥5% of patients treated with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg, and more commonly than in patients treated with placebo are shown in Table 9. See Table 9.

In patients treated with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 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 (Kombiglyze XR 2.5mg/1000mg) 2.5 mg or Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg and ≥1% more frequently compared to placebo included: Sinusitis (2.9% and 2.6% vs 1.6%, respectively), abdominal pain (2.4% and 1.7% vs 0.5%), gastroenteritis (1.9% and 2.3% vs 0.9%), and vomiting (2.2% and 2.3% vs 1.3%).

The incidence rate of fractures was 1 and 0.6 per 100 patient years, respectively, for Saxagliptin (Kombiglyze XR 2.5mg/1000mg) (pooled analysis of 2.5 mg, 5 mg and 10 mg) and placebo. The incidence rate of fracture events in patients who received Saxagliptin (Kombiglyze XR 2.5mg/1000mg) did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 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 (Kombiglyze XR 2.5mg/1000mg) is not known.

Use in Combination with Insulin: 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 (Kombiglyze XR 2.5mg/1000mg) and placebo, except for confirmed hypoglycemia.

Adverse Reactions Associated with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) Co-Administered with Metformin (Kombiglyze XR 2.5mg/1000mg) Immediate-Release in Treatment-Naive Patients with Type 2 Diabetes: Table 10 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 co-administered Saxagliptin (Kombiglyze XR 2.5mg/1000mg) and Metformin (Kombiglyze XR 2.5mg/1000mg) in treatment-naive patients. See Table 10.

In patients treated with the combination of Saxagliptin (Kombiglyze XR 2.5mg/1000mg) and Metformin (Kombiglyze XR 2.5mg/1000mg) immediate-release, either as Saxagliptin (Kombiglyze XR 2.5mg/1000mg) add-on to Metformin (Kombiglyze XR 2.5mg/1000mg) immediate-release therapy or as co-administration 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 (Kombiglyze XR 2.5mg/1000mg) add-on to Metformin (Kombiglyze XR 2.5mg/1000mg) immediate-release trial, the incidence of diarrhea was 9.9%, 5.8% and 11.2% in the Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 2.5 mg, 5 mg, and placebo groups, respectively. When Saxagliptin (Kombiglyze XR 2.5mg/1000mg) and Metformin (Kombiglyze XR 2.5mg/1000mg) immediate-release were co-administered in treatment-naive patients, the incidence of diarrhea was 6.9% in the Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg + Metformin (Kombiglyze XR 2.5mg/1000mg) immediate-release group and 7.3% in the placebo + Metformin (Kombiglyze XR 2.5mg/1000mg) immediate-release group.

Hypoglycemia: In the Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 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 (Kombiglyze XR 2.5mg/1000mg) 2.5 mg and Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg vs placebo given as monotherapy was 4% and 5.6% vs 4.1%, respectively. In the add-on to Metformin (Kombiglyze XR 2.5mg/1000mg) immediate-release trial, the incidence of reported hypoglycemia was 7.8% with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 2.5 mg, 5.8% with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg, and 5% with placebo. When Saxagliptin (Kombiglyze XR 2.5mg/1000mg) and Metformin (Kombiglyze XR 2.5mg/1000mg) immediate-release were co-administered in treatment-naive patients, the incidence of reported hypoglycemia was 3.4% in patients given Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg + Metformin (Kombiglyze XR 2.5mg/1000mg) immediate-release and 4% in patients given placebo + Metformin (Kombiglyze XR 2.5mg/1000mg) immediate-release.

In the active-controlled trial comparing add-on therapy with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg to glipizide in patients inadequately controlled on Metformin (Kombiglyze XR 2.5mg/1000mg) alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg vs 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 (Kombiglyze XR 2.5mg/1000mg)-treated patients and in 35 glipizide-treated patients (8.1%) (p<0.0001).

In the add-on to insulin trial, the overall incidence of reported hypoglycemia was 18.4% for Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 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 (Kombiglyze XR 2.5mg/1000mg) 5 mg (5.3%) vs placebo (3.3%). Among the patients using insulin in combination with Metformin (Kombiglyze XR 2.5mg/1000mg), the incidence of confirmed symptomatic hypoglycemia was 4.8% with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) vs 1.9% with placebo.

Hypersensitivity Reactions: Saxagliptin (Kombiglyze XR 2.5mg/1000mg): Hypersensitivity-related events eg, urticaria and facial edema in the 5S pooled analysis up to week 24 were reported in 1.5%, 1.5%, and 0.4% of patients who received Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 2.5 mg, Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg, and placebo, respectively. None of these events in patients who received Saxagliptin (Kombiglyze XR 2.5mg/1000mg) required hospitalization or were reported as life-threatening by the investigators. One Saxagliptin (Kombiglyze XR 2.5mg/1000mg)-treated patient in this pooled analysis discontinued due to generalized urticaria and facial edema.

Infections: Saxagliptin (Kombiglyze XR 2.5mg/1000mg): In the unblinded, controlled, clinical trial database for Saxagliptin (Kombiglyze XR 2.5mg/1000mg) to date, there have been 6 (0.12%) reports of tuberculosis among the 4959 Saxagliptin (Kombiglyze XR 2.5mg/1000mg)-treated patients (1.1/1000 patient years) compared to no reports of tuberculosis among the 2868 comparator-treated patients. Two of these 6 cases were confirmed with laboratory testing. The remaining cases had limited information or had presumptive diagnoses of tuberculosis. None of the 6 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 (Kombiglyze XR 2.5mg/1000mg) until report of tuberculosis ranged from 144-929 days. Posttreatment lymphocyte counts were consistently within the reference range for 4 cases. One patient had lymphopenia prior to initiation of Saxagliptin (Kombiglyze XR 2.5mg/1000mg) that remained stable throughout Saxagliptin (Kombiglyze XR 2.5mg/1000mg) treatment. The final patient had an isolated lymphocyte count below normal approximately 4 months prior to the report of tuberculosis. There have been no spontaneous reports of tuberculosis associated with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) use. Causality has not been established and there are too few cases to date to determine whether tuberculosis is related to Saxagliptin (Kombiglyze XR 2.5mg/1000mg) use.

There has been 1 case of a potential opportunistic infection in the unblinded, controlled clinical trial database to date in a Saxagliptin (Kombiglyze XR 2.5mg/1000mg)-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of Saxagliptin (Kombiglyze XR 2.5mg/1000mg) therapy. There have been no spontaneous reports of opportunistic infections associated with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) use.

Vital Signs: Saxagliptin (Kombiglyze XR 2.5mg/1000mg): No clinically meaningful changes in vital signs have been observed in patients treated with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) alone or in combination with Metformin (Kombiglyze XR 2.5mg/1000mg).

Laboratory Tests: Absolute Lymphocyte Counts: Saxagliptin (Kombiglyze XR 2.5mg/1000mg): There was a dose-related mean decrease in absolute lymphocyte count observed with Saxagliptin (Kombiglyze XR 2.5mg/1000mg). From a baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 cells/microL and 120 cells/microL with Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in a pooled analysis of 5 placebo-controlled clinical studies. Similar effects were observed when Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 5 mg and Metformin (Kombiglyze XR 2.5mg/1000mg) were co-administered in treatment-naive patients compared to placebo and Metformin (Kombiglyze XR 2.5mg/1000mg). There was no difference observed for Saxagliptin (Kombiglyze XR 2.5mg/1000mg) 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 (Kombiglyze XR 2.5mg/1000mg) 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to Saxagliptin (Kombiglyze XR 2.5mg/1000mg) although some patients had recurrent decreases upon rechallenge that led to discontinuation of Saxagliptin (Kombiglyze XR 2.5mg/1000mg). The decreases in lymphocyte count were not associated with clinically relevant adverse reactions.

The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated eg, in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of Saxagliptin (Kombiglyze XR 2.5mg/1000mg) on lymphocyte counts in patients with lymphocyte abnormalities (eg, human immunodeficiency virus) is unknown.

Platelets: Saxagliptin (Kombiglyze XR 2.5mg/1000mg): Saxagliptin (Kombiglyze XR 2.5mg/1000mg) did not demonstrate a clinically meaningful or consistent effect on platelet count in the 6, double-blind, controlled clinical safety and efficacy trials.

Vitamin B₁₂ Concentrations: Metformin (Kombiglyze XR 2.5mg/1000mg) HCl: Metformin (Kombiglyze XR 2.5mg/1000mg) may lower serum vitamin B₁₂ concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on Kombiglyze XR 2.5mg/1000mg and any apparent abnormalities should be appropriately investigated and managed.

Post-Marketing Experience: Additional adverse reactions have been identified during postapproval use of Saxagliptin (Kombiglyze XR 2.5mg/1000mg). 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.

Kombiglyze XR 2.5mg/1000mg (Saxagliptin (Kombiglyze XR 2.5mg/1000mg) and Metformin (Kombiglyze XR 2.5mg/1000mg) HCl extended-release) tablets contain two oral antihyperglycemic medications used in the management of type 2 diabetes: Saxagliptin (Kombiglyze XR 2.5mg/1000mg) and Metformin (Kombiglyze XR 2.5mg/1000mg) hydrochloride.

Saxagliptin (Kombiglyze XR 2.5mg/1000mg): Saxagliptin (Kombiglyze XR 2.5mg/1000mg) is an orally-active inhibitor of the dipeptidyl-peptidase-4 (DPP4) enzyme.

Saxagliptin (Kombiglyze XR 2.5mg/1000mg) monohydrate 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 C₁₈H₂₅N₃O₂·H₂O and the molecular weight is 333.43.

Saxagliptin (Kombiglyze XR 2.5mg/1000mg) monohydrate is 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 (Kombiglyze XR 2.5mg/1000mg) Hydrochloride: Metformin (Kombiglyze XR 2.5mg/1000mg) hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a white to off-white crystalline compound with a molecular formula of C₄H₁₁N₅·HCl and a molecular weight of 165.63. Metformin (Kombiglyze XR 2.5mg/1000mg) hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pKa of Metformin (Kombiglyze XR 2.5mg/1000mg) is 12.4. The pH of a 1% aqueous solution of Metformin (Kombiglyze XR 2.5mg/1000mg) hydrochloride is 6.68.

Kombiglyze XR 2.5mg/1000mg: Kombiglyze XR 2.5mg/1000mg is available for oral administration as tablets containing either 5.58mg Saxagliptin (Kombiglyze XR 2.5mg/1000mg) hydrochloride (anhydrous) equivalent to 5 mg Saxagliptin (Kombiglyze XR 2.5mg/1000mg) and 500 mg Metformin (Kombiglyze XR 2.5mg/1000mg) hydrochloride (Kombiglyze XR 2.5mg/1000mg 5 mg/500 mg), or 5.58 mg Saxagliptin (Kombiglyze XR 2.5mg/1000mg) hydrochloride (anhydrous) equivalent to 5 mg Saxagliptin (Kombiglyze XR 2.5mg/1000mg) and 1000 mg Metformin (Kombiglyze XR 2.5mg/1000mg) hydrochloride (Kombiglyze XR 2.5mg/1000mg 5 mg/1000 mg), or 2.79 mg Saxagliptin (Kombiglyze XR 2.5mg/1000mg) hydrochloride (anhydrous) equivalent to 2.5 mg Saxagliptin (Kombiglyze XR 2.5mg/1000mg) and 1000 mg Metformin (Kombiglyze XR 2.5mg/1000mg) hydrochloride (Kombiglyze XR 2.5mg/1000mg 2.5 mg/1000 mg). Each film-coated tablet of Kombiglyze XR 2.5mg/1000mg contains the following inactive ingredients: Carboxymethylcellulose sodium, hypromellose 2208, and magnesium stearate. The 5 mg/500 mg strength tablet of Kombiglyze XR 2.5mg/1000mg also contains microcrystalline cellulose and hypromellose 2910. In addition, the film coatings contain the following inactive ingredients: polyvinyl alcohol, polyethylene glycol 3350, titanium dioxide, talc, iron oxides and traces of FD&C#2/Indigo carmine aluminium and shellac.

The biologically inert components of the tablet may occasionally remain intact during gastrointestinal transit and will be eliminated in the feces as a soft, hydrated mass.

Excipients/Inactive Ingredients: Carboxymethylcellulose sodium, hypromellose 2208, magnesium stearate, polyvinyl alcohol, polyethylene glycol 3350, titanium dioxide, talc, iron oxides, traces of FD&C #2/indigo carmine aluminium, traces of shellac, *microcrystalline cellulose, *hypromellose 2910 (*these excipients are present only in the 5 mg/500 mg strength tablet of Kombiglyze XR 2.5mg/1000mg).