Kombiglyze XR

/ Astra Zeneca

The dosage should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability. This drug should generally be administered once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with Metformin.
The recommended starting dose 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 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 this product  in patients previously treated with other antihyperglycemic medications and switched to it. 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 tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet.
Dosage Adjustments with Concomitant Use of Strong CYP3A4/5 Inhibitors: 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.
Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with
Insulin: 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.

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.
Limitations of Use: 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.

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 this product or Saxagliptin, such as anaphylaxis, angioedema, or exfoliative skin conditions.

Lactic acidosis: Lactic acidosis is is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment; 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.
Pancreatitis: There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin. After initiation, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, this product 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 it.
Assessment of Renal Function: 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, it is contraindicated in patients with renal impairment.
Impaired Hepatic Function: Metformin use in patients with impaired hepatic function has been associated with some cases of lactic acidosis. Therefore, it is not recommended in patients with hepatic impairment.
Vitamin B12 Concentrations: Measurement of hematologic parameters on an annual basis is advised in patients on on this product 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 Intake: Alcohol potentiates the effect of Metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving this drug.
Surgical Procedures: Use of this product 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.
Radiologic Studies with Intravascular Iodinated Contrast Materials: 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, it 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.
Hypersensitivity Reactions: 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 this produt, 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 this product.
See prescribing information for full details.

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.
See prescribing information for full details.

Strong Inhibitors of CYP3A4/5 Enzymes
Saxagliptin: 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
Metformin 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 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.
Use with Other Drugs
Metformin hydrochloride: Some medications can predispose to hyperglycemia and may lead to loss of glycemic control.
These medications include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving KOMBIGLYZE XR, the patient should be closely observed for loss of glycemic control. When such drugs are withdrawn from a patient receiving KOMBIGLYZE XR, the patient should be observed closely for hypoglycemia.

Pregnancy: 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.
Lactation: No studies in lactating animals have been conducted with this drug. 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.
See prescribing information for full details.

Saxagliptin: 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).
Metformin hydrochloride: 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 overdose is suspected.

Shelf life: 3 years.
Storage: Store below 30°C.