Sitagliptin And Metformin Hydrochloride

Sitagliptin And Metformin Hydrochloride
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]

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Black Box Warning

WARNING: LACTIC ACIDOSIS See full prescribing information for complete Boxed 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 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, sitagliptin and metformin hydrochloride should be discontinued and the patient hospitalized immediately.

Overview

Sitagliptin And Metformin Hydrochloride is a anti-diabetic drug that is FDA approved for the treatment of diabetes mellitus type 2. There is a Black Box Warning for this drug as shown here. Common adverse reactions include asthenia, headache, nasopharyngitis.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• The dosage of sitagliptin and metformin should be individualized on the basis of the patient's current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.
• Sitagliptin and metformin should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects due to metformin. Sitagliptin and metformin must not be split or divided before swallowing.
• The starting dose of sitagliptin and metformin should be based on the patient's current regimen. Sitagliptin and metformin should be given twice daily with meals. The following doses are available:

• 50 mg sitagliptin/500 mg metformin hydrochloride
• 50 mg sitagliptin/1000 mg metformin hydrochloride

• The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin.
• The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of sitagliptin and metformin is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.
• Patients treated with an insulin secretagogue or insulin.
• Coadministration of sitagliptin and metformin with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
• No studies have been performed specifically examining the safety and efficacy of sitagliptin and metformin in patients previously treated with other oral antihyperglycemic agents and switched to sitagliptin and metformin . Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Sitagliptin And Metformin Hydrochloride in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sitagliptin And Metformin Hydrochloride in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Sitagliptin And Metformin Hydrochloride FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Sitagliptin And Metformin Hydrochloride in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sitagliptin And Metformin Hydrochloride in pediatric patients.

Contraindications

Sitagliptin and metformin is contraindicated in patients with:

• Renal impairment (e.g., serum creatinine levels greater than or equal to 1.5 mg/dL for men, greater than or equal to 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.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.
• History of a serious hypersensitivity reaction to Sitagliptin or metformin, such as anaphylaxis or angioedema.

Warnings

WARNING: LACTIC ACIDOSIS See full prescribing information for complete Boxed 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 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, sitagliptin and metformin hydrochloride should be discontinued and the patient hospitalized immediately.

Lactic Acidosis

Metformin hydrochloride Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUMET; 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 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 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. 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, either acute or chronic, 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 [see Warnings and Precautions (5.4, 5.6, 5.7, 5.11)]. 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 [see Warnings and Precautions (5.12)]. 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 [see Warnings and Precautions (5.8, 5.13)]. 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 [see Contraindications (4); Warnings and Precautions (5.6, 5.7, 5.10, 5.11, 5.12)].

Pancreatitis

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUMET. After initiation of JANUMET, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUMET 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 JANUMET.

Impaired Hepatic Function

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

Assessment of Renal Function

Metformin and sitagliptin are known to be substantially excreted by the kidney. Metformin hydrochloride The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Therefore, JANUMET is contraindicated in patients with renal impairment. Before initiation of JANUMET and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated (e.g., elderly), renal function should be assessed more frequently and JANUMET discontinued if evidence of renal impairment is present. Sitagliptin There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy with JANUMET 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 discontinued if evidence of renal impairment is present.

Vitamin B12 Levels

In controlled clinical trials of metformin of 29 weeks 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 JANUMET and any apparent abnormalities should be appropriately investigated and managed. [See Adverse Reactions (6.1).] 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 two- to three-year intervals may be useful.

Alcohol Intake

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving JANUMET.

Surgical Procedures

Use of JANUMET 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. 5.8 Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes A patient with type 2 diabetes previously well controlled on JANUMET 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, JANUMET must be stopped immediately and other appropriate corrective measures initiated.

Use with Medications Known to Cause Hypoglycemia

Sitagliptin When sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin [see Adverse Reactions (6)]. Therefore, patients also receiving an insulin secretagogue (e.g., sulfonylurea) or insulin may require a lower dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Dosage and Administration (2.1)]. 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. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs.

Concomitant Medications Affecting Renal Function or Metformin Disposition

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 [see Drug Interactions (7.2)], should be used with caution.

Radiologic Studies with Intravascular Iodinated Contrast Materials

Intravascular contrast studies with iodinated materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin [see Contraindications (4)]. Therefore, in patients in whom any such study is planned, JANUMET 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.

Hypoxic States

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 therapy, the drug should be promptly discontinued.

Loss of Control of Blood Glucose

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold JANUMET and temporarily administer insulin. JANUMET may be reinstituted after the acute episode is resolved.

Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET. These reactions include 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, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See Adverse Reactions (6.2).] Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUMET.

Macrovascular Outcomes

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

Adverse Reactions

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Sitagliptin And Metformin Hydrochloride
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Storage

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Patient Counseling Information

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Precautions with Alcohol

Alcohol-Sitagliptin And Metformin Hydrochloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Sitagliptin And Metformin Hydrochloride Brand Names in the drug label.

Look-Alike Drug Names

• (Paired Confused Name 1a) — (Paired Confused Name 1b)
• (Paired Confused Name 2a) — (Paired Confused Name 2b)
• (Paired Confused Name 3a) — (Paired Confused Name 3b)

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References

The contents of this FDA label are provided by the National Library of Medicine.