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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, JANUMET XR should be discontinued and the patient hospitalized immediately [see Warnings and Precautions].


Contraindications
JANUMET XR is contraindicated in patients with renal impairment (serum creatinine levels >1.5 mg/dL in men and >1.4 mg/dL in women or abnormal creatinine clearance); hypersensitivity to metformin hydrochloride; acute or chronic metabolic acidosis, including diabetic ketoacidosis; or history of a serious hypersensitivity reaction to JANUMET XR or sitagliptin, such as anaphylaxis or angioedema.

Warnings and Precautions
There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis.

Before initiation of therapy with JANUMET XR and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET XR discontinued if evidence of renal impairment is present.

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.

Cardiovascular collapse (shock) from whatever cause, 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 JANUMET XR therapy, the drug should be promptly discontinued.

Lactic acidosis is fatal in approximately 50% of cases. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years. Reported cases have occurred primarily in diabetic patients with significant renal impairment, 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 JANUMET XR. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.

There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin with or without metformin. After initiating JANUMET XR, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JANUMET XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUMET XR.

Use of JANUMET 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.

Measurement of hematologic parameters on an annual basis is advised in patients on JANUMET 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.

Since impaired hepatic function has been associated with some cases of lactic acidosis, JANUMET XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

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

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, JANUMET XR should be temporarily discontinued at the time of or before the procedure, withheld for 48 hours subsequent to the procedure, and reinstituted only after renal function has been re-evaluated and found to be normal.

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

Use With Medications Known to Cause Hypoglycemia
Sitagliptin
When sitagliptin was used in combination with a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or insulin. Therefore, patients also receiving insulin or an insulin secretagogue (eg, sulfonylurea) may require a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia.

The incidence (and rate) of hypoglycemia based on all reports of symptomatic hypoglycemia were: 16.4% (0.82 episodes/patient-year) for sitagliptin 100 mg in combination with metformin and glimepiride, 0.9% (0.02 episodes/patient-year) for placebo in combination with metformin and glimepiride, 8.2% (0.61 episodes/patient-year) for placebo in combination with metformin and insulin, and 15.3% (0.98 episodes/patient-year) for sitagliptin in combination with metformin and insulin.

Adverse reactions with sitagliptin in combination with metformin and rosiglitazone through Week 18 were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54 they were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).

Metformin hydrochloride
Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. When such drugs are administered to a patient receiving JANUMET XR, the patient should be closely observed to maintain adequate glycemic control.

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET XR, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUMET 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 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUMET XR.

Adverse Reactions
In clinical studies, the most common adverse reactions reported, regardless of investigator assessment of causality, in >5% of patients treated with either sitagliptin in combination with metformin or placebo were as follows: diarrhea (7.5% vs 4.0%), upper respiratory tract infection (6.2% vs 5.1%), and headache (5.9% vs 2.8%). In patients treated with sitagliptin in combination with metformin and sulfonylurea or placebo in combination with metformin and sulfonylurea: hypoglycemia (16.4% vs 0.9%) and headache (6.9% vs 2.7%). In patients treated with sitagliptin in combination with metformin and insulin or placebo in combination with metformin and insulin: hypoglycemia (15.3% vs 8.2%). Other adverse events with an incidence of >5% included nasopharyngitis for sitagliptin monotherapy and hypoglycemia (13.7% vs 4.9%), diarrhea (12.5% vs 5.6%), and nausea (6.7% vs 4.2%) for extended-release metformin vs placebo when added to glyburide.

The incidence of selected gastrointestinal adverse reactions in patients treated with sitagliptin and metformin was similar to those of placebo and metformin: nausea (1.3%, 0.8%), vomiting (1.1%, 0.8%), abdominal pain (2.2%, 3.8%), and diarrhea (2.4%, 2.5%).

Use in Specific Populations

Because sitagliptin and metformin are substantially excreted by the kidney, and because aging can be associated with reduced renal function, JANUMET XR should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function.

There are no adequate and well-controlled studies in pregnant women with JANUMET XR or its individual components; therefore, the safety of JANUMET XR in pregnant women is not known. JANUMET XR should be used during pregnancy only if clearly needed.

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to JANUMET XR while pregnant. Health care providers are encouraged to report any prenatal exposure to JANUMET XR by calling the Pregnancy Registry at 1-800-986-8999.

No studies in lactating animals have been conducted with the combined components of JANUMET XR. Because many drugs are excreted in human milk, caution should be exercised when JANUMET XR is administered to a nursing woman.

Safety and effectiveness of JANUMET XR in children under 18 years have not been established.