ONGLYZA®
(saxagliptin)

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WARNING FOR KOMBIGLYZE XR: LACTIC ACIDOSIS US Full Prescribing Information including Boxed WARNING about lactic acidosis, and Medication Guide

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

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

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

If acidosis is suspected, KOMBIGLYZE™ XR (saxagliptin and metformin HCl extended-release) should be discontinued and the patient hospitalized immediately. [See Warnings and Precautions]

Generally taken once daily with evening meal; gradually titrate dose to reduce GI side effects associated with metformin. Maximum daily recommended dose is
5 mg saxagliptin and 2000 mg metformin XR that can be taken as two 2.5/1000 mg tablets once a day.

For your appropriate adult patients with type 2 diabetes in addition to diet and exercise

Kombiglyze™ XR (saxagliptin and metformin HCI extended-release) provides the convenience of once-a-day dosing with multiple dosing options for you including a starting dose of 500 mg of metformin XR

*Tablets not actual size

  • Tablets must be swallowed whole and never crushed, cut or chewed.
  • Generally taken once daily with evening meal; gradually titrate dose to reduce GI side effects associated with metformin.
  • Occasionally, the inactive ingredients of Kombiglyze XR (saxagliptin and metformin HCI extended-release) will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet.
  • Contraindicated in patients with renal impairment (eg, serum creatinine levels ≥1.5 mg/dL for men,
    ≥1.4 mg/dL for women, or abnormal creatinine clearance), hypersensitivity to metformin hydrochloride, metabolic acidosis (including diabetic ketoacidosis), and history of a serious hypersensitivity reaction to Kombiglyze XR or saxagliptin (eg, anaphylaxis, angioedema, or exfoliative skin conditions).
  • Temporarily discontinue in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials.

Recommended Starting Dose

In patients who need 5 mg of saxagliptin and who are not currently treated with metformin, the recommended starting dose of Kombiglyze XR is 5 mg saxagliptin/500 mg metformin extended-release once daily.

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

Patients who need 2.5 mg saxagliptin, may be treated with Kombiglyze XR 2.5/1000 mg. If they are metformin-naive or require a higher dose of metformin, individual components should be used.


Maximum Recommended Dose

Maximum daily recommended dose is 5 mg saxagliptin and 2000 mg metformin XR that can be taken as two 2.5/1000 mg tablets once a day.

Drug Interactions

  • Limit the saxagliptin dose to 2.5 mg daily for patients also taking strong CYP3A4/5 inhibitors (eg, ketoconazole).
  • Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination; use with caution.

Use in Specific Populations

  • Pregnant and Nursing Women: There are no adequate and well-controlled studies in pregnant women. Kombiglyze XR should be used during pregnancy only if clearly needed. 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.
  • Pediatric Patients: Safety and effectiveness of Kombiglyze XR in pediatric patients have not been established.
WARNING: LACTIC ACIDOSIS
Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure.
The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.
Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.
If acidosis is suspected, KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release) should be discontinued and the patient hospitalized immediately. [See Warnings and Precautions]

Contraindications

  • Renal impairment (eg, serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or abnormal creatinine clearance)
  • Hypersensitivity to metformin hydrochloride
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis
  • History of a serious hypersensitivity reaction to KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release) or saxagliptin (eg, anaphylaxis, angioedema, or exfoliative skin conditions)

Warnings and Precautions

  • The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases/1000 patient-years). When it occurs, it is fatal in approximately 50% of cases. Reported cases of lactic acidosis have occurred primarily in diabetic patients with significant renal insufficiency.
  • 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.
  • Lactic acidosis risk increases with the degree of renal dysfunction and patient age. The risk may be significantly decreased by use of minimum effective dose of metformin and regular monitoring of renal function. Careful renal monitoring is particularly important in the elderly. KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release) should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.
  • Withhold KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release) in the presence of any condition associated with hypoxemia, dehydration, or sepsis.
  • There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin. After initiating KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release), observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release)and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while using KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release).
  • Before initiation of KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release), and at least annually thereafter, renal function should be assessed and verified as normal.
  • KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release) is not recommended in patients with hepatic impairment.
  • Metformin may lower vitamin B12 levels. Measure hematological parameters annually.
  • Warn patients against excessive alcohol intake.
  • KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release) should be suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids), and should not be restarted until patient's oral intake has resumed and renal function is normal.
  • Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
Saxagliptin: 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 (saxagliptin and metformin HCI extended-release).
Metformin: 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, during concomitant use with other glucose-lowering agents (such as sulfonylureas or insulin), or with use of ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.
  • 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. KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release) should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours after the procedure and reinstituted only after renal function is normal.
  • There have been postmarketing reports of serious hypersensitivity reactions in patients treated with saxagliptin, including 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 (saxagliptin and metformin HCI extended-release), assess for other potential causes for the event, and institute alternative treatment for diabetes. Use caution in patients with a history of angioedema to another DPP-4 inhibitor as it is unknown whether they will be predisposed to angioedema with KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release).
  • There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release) or any other anti-diabetic drug.

Adverse Reactions

  • Adverse reactions reported in >5% of patients treated with metformin extended-release and more commonly than in patients treated with placebo were: diarrhea (9.6% vs 2.6%) and nausea/vomiting (6.5% vs 1.5%).
  • Adverse reactions reported in ≥5% of patients treated with saxagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (7.7% vs 7.6%), urinary tract infection (6.8% vs 6.1%), and headache (6.5% vs 5.9%).
  • Adverse reactions reported in ≥5% of treatment-naive patients treated with coadministered saxagliptin and metformin immediate-release (IR) and more commonly than in patients treated with metformin IR alone were: headache (7.5% vs 5.2%) and nasopharyngitis (6.9% vs 4.0%).
  • Confirmed hypoglycemia was reported more commonly in patients treated with saxagliptin 5 mg compared to placebo in the add-on to insulin (with or without metformin) trial (5.3% and 3.3%, respectively). Among the patients using insulin with metformin, the incidence of confirmed hypoglycemia was 4.8% with saxagliptin vs 1.9% with placebo. Confirmed hypoglycemia was reported more commonly with saxagliptin 5 mg compared to placebo in the add-on to metformin plus sulfonylurea trial (1.6% and 0.0%, respectively).

Drug Interactions

Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin exposure, limit KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release) to 2.5 mg/1000 mg once daily when coadministered with a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).

Use in Specific Populations

  • Pregnant and Nursing Women: There are no adequate and well-controlled studies in pregnant women. KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release) should be used during pregnancy only if clearly needed. 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 (saxagliptin and metformin HCI extended-release) is administered to a nursing woman.
  • Pediatric Patients: Safety and effectiveness of KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release) in pediatric patients have not been established.
KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release) 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 (saxagliptin and metformin HCI extended-release) should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
KOMBIGLYZE™ XR (saxagliptin and metformin HCI extended-release) has not been studied in patients with a history of pancreatitis.

Please click here for US Full Prescribing Information for KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) (5/500•5/1000•2.5/1000 mg tablets), including Boxed WARNING about lactic acidosis, and Medication Guide
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