Sitagliptin And Metformin Hydrochloride Prescribing Information
WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions ( 5.1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels were generally >5 mcg/mL Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of sitagliptin and metformin hydrochloride extended-release tablets. In sitagliptin and metformin hydrochloride extended-release tablet-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis, and if these symptoms occur instruct them to discontinue sitagliptin and metformin hydrochloride extended-release tablets and report these symptoms to their health care provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration and Clinical Pharmacology ] :
Drug Interactions The concomitant use of sitagliptin and metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions ]. Therefore, consider more frequent monitoring of patients.Age 65 or Greater The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations ]. Radiological Studies with Contrast Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop sitagliptin and metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart sitagliptin and metformin hydrochloride extended-release tablets if renal function is stable. Surgery and Other Procedures Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Sitagliptin and metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue sitagliptin and metformin hydrochloride extended-release tablets. Excessive Alcohol Intake Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving sitagliptin and metformin hydrochloride extended-release tablets. Hepatic Impairment Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of sitagliptin and metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2), Contraindications ( Sitagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with:
5.1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels were generally >5 mcg/mL Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of sitagliptin and metformin hydrochloride extended-release tablets. In sitagliptin and metformin hydrochloride extended-release tablet-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis, and if these symptoms occur instruct them to discontinue sitagliptin and metformin hydrochloride extended-release tablets and report these symptoms to their health care provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration and Clinical Pharmacology ] :
Drug Interactions The concomitant use of sitagliptin and metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions ]. Therefore, consider more frequent monitoring of patients.Age 65 or Greater The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations ]. Radiological Studies with Contrast Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop sitagliptin and metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart sitagliptin and metformin hydrochloride extended-release tablets if renal function is stable. Surgery and Other Procedures Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Sitagliptin and metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue sitagliptin and metformin hydrochloride extended-release tablets. Excessive Alcohol Intake Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving sitagliptin and metformin hydrochloride extended-release tablets. Hepatic Impairment Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of sitagliptin and metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease. Table 4 presents clinically significant drug interactions with sitagliptin and metformin hydrochloride extended-release tablets:
8.6 Renal Impairment Sitagliptin and metformin hydrochloride extended-release tablets The dose of the sitagliptin component should be limited to 50 mg once daily if eGFR falls below 45 mL/min/1.73 m2. Sitagliptin and metformin hydrochloride extended-release tablets is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m2 [see Dosage and Administration , Contraindications , Warnings and Precautions and Clinical Pharmacology ]. Sitagliptin Sitagliptin is excreted by the kidney, and sitagliptin exposure is increased in patients with renal impairment [see Clinical Pharmacology ]. Metformin Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. 8.7 Hepatic Impairment Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Sitagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)]. If metformin-associated lactic acidosis is suspected, immediately discontinue sitagliptin and metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions ( 5.1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels were generally >5 mcg/mL Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of sitagliptin and metformin hydrochloride extended-release tablets. In sitagliptin and metformin hydrochloride extended-release tablet-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis, and if these symptoms occur instruct them to discontinue sitagliptin and metformin hydrochloride extended-release tablets and report these symptoms to their health care provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration and Clinical Pharmacology ] :
Drug Interactions The concomitant use of sitagliptin and metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions ]. Therefore, consider more frequent monitoring of patients.Age 65 or Greater The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations ]. Radiological Studies with Contrast Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop sitagliptin and metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart sitagliptin and metformin hydrochloride extended-release tablets if renal function is stable. Surgery and Other Procedures Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Sitagliptin and metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue sitagliptin and metformin hydrochloride extended-release tablets. Excessive Alcohol Intake Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving sitagliptin and metformin hydrochloride extended-release tablets. Hepatic Impairment Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of sitagliptin and metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sitagliptin and metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Sitagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with type 1 diabetes mellitus.
Sitagliptin and metformin hydrochloride extended-release tablets have not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using sitagliptin and metformin hydrochloride extended-release tablets
There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin with or without metformin. After initiation of sitagliptin and metformin hydrochloride extended-release tablets, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, sitagliptin and metformin hydrochloride extended-release tablets 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 sitagliptin and metformin hydrochloride extended-release tablets.
- Take sitagliptin and metformin hydrochloride extended-release tablets orally once daily with a meal. Patients taking two sitagliptin and metformin hydrochloride extended-release tablets should take the tablets together. ()2.1 Recommended Dosage and Administration
- Take sitagliptin and metformin hydrochloride extended-release tablets orally once daily with a meal. Patients taking two sitagliptin and metformin hydrochloride extended-release tablets should take the two tablets together once daily.
- Individualize the dosage of sitagliptin and metformin hydrochloride extended-release tablets on the basis of the patient's current regimen, effectiveness, and tolerability.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin hydrochloride (HCl) extended-release.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release once 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 100 mg sitagliptin and the previously prescribed dose of metformin.
- For patients taking metformin hydrochloride immediate-release 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of sitagliptin and metformin hydrochloride extended-release tablets are two 50 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets taken together once daily.
- Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin hydrochloride immediate-release or sitagliptin and metformin extended-release and sitagliptin and metformin hydrochloride extended-release tablets.
- Do not split, crush or chew sitagliptin and metformin hydrochloride extended-release tablets.
- Individualize the dosage of sitagliptin and metformin hydrochloride extended-release tablets on the basis of the patient's current regimen, effectiveness, and tolerability. ()2.1 Recommended Dosage and Administration
- Take sitagliptin and metformin hydrochloride extended-release tablets orally once daily with a meal. Patients taking two sitagliptin and metformin hydrochloride extended-release tablets should take the two tablets together once daily.
- Individualize the dosage of sitagliptin and metformin hydrochloride extended-release tablets on the basis of the patient's current regimen, effectiveness, and tolerability.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin hydrochloride (HCl) extended-release.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release once 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 100 mg sitagliptin and the previously prescribed dose of metformin.
- For patients taking metformin hydrochloride immediate-release 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of sitagliptin and metformin hydrochloride extended-release tablets are two 50 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets taken together once daily.
- Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin hydrochloride immediate-release or sitagliptin and metformin extended-release and sitagliptin and metformin hydrochloride extended-release tablets.
- Do not split, crush or chew sitagliptin and metformin hydrochloride extended-release tablets.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin hydrochloride extended-release. ()2.1 Recommended Dosage and Administration
- Take sitagliptin and metformin hydrochloride extended-release tablets orally once daily with a meal. Patients taking two sitagliptin and metformin hydrochloride extended-release tablets should take the two tablets together once daily.
- Individualize the dosage of sitagliptin and metformin hydrochloride extended-release tablets on the basis of the patient's current regimen, effectiveness, and tolerability.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin hydrochloride (HCl) extended-release.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release once 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 100 mg sitagliptin and the previously prescribed dose of metformin.
- For patients taking metformin hydrochloride immediate-release 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of sitagliptin and metformin hydrochloride extended-release tablets are two 50 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets taken together once daily.
- Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin hydrochloride immediate-release or sitagliptin and metformin extended-release and sitagliptin and metformin hydrochloride extended-release tablets.
- Do not split, crush or chew sitagliptin and metformin hydrochloride extended-release tablets.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin hydrochloride once daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin. ()2.1 Recommended Dosage and Administration
- Take sitagliptin and metformin hydrochloride extended-release tablets orally once daily with a meal. Patients taking two sitagliptin and metformin hydrochloride extended-release tablets should take the two tablets together once daily.
- Individualize the dosage of sitagliptin and metformin hydrochloride extended-release tablets on the basis of the patient's current regimen, effectiveness, and tolerability.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin hydrochloride (HCl) extended-release.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release once 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 100 mg sitagliptin and the previously prescribed dose of metformin.
- For patients taking metformin hydrochloride immediate-release 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of sitagliptin and metformin hydrochloride extended-release tablets are two 50 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets taken together once daily.
- Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin hydrochloride immediate-release or sitagliptin and metformin extended-release and sitagliptin and metformin hydrochloride extended-release tablets.
- Do not split, crush or chew sitagliptin and metformin hydrochloride extended-release tablets.
- The starting dose in patients already treated with metformin should provide sitagliptin dosed as 100 mg and the dose of metformin already being taken once daily. For patients taking metformin hydrochloride 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of sitagliptin and metformin hydrochloride extended-release tablets are two 50 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets once daily. ()2.1 Recommended Dosage and Administration
- Take sitagliptin and metformin hydrochloride extended-release tablets orally once daily with a meal. Patients taking two sitagliptin and metformin hydrochloride extended-release tablets should take the two tablets together once daily.
- Individualize the dosage of sitagliptin and metformin hydrochloride extended-release tablets on the basis of the patient's current regimen, effectiveness, and tolerability.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin hydrochloride (HCl) extended-release.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release once 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 100 mg sitagliptin and the previously prescribed dose of metformin.
- For patients taking metformin hydrochloride immediate-release 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of sitagliptin and metformin hydrochloride extended-release tablets are two 50 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets taken together once daily.
- Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin hydrochloride immediate-release or sitagliptin and metformin extended-release and sitagliptin and metformin hydrochloride extended-release tablets.
- Do not split, crush or chew sitagliptin and metformin hydrochloride extended-release tablets.
- Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin immediate-release or sitagliptin and metformin extended-release and sitagliptin and metformin hydrochloride extended-release tablets. ()2.1 Recommended Dosage and Administration
- Take sitagliptin and metformin hydrochloride extended-release tablets orally once daily with a meal. Patients taking two sitagliptin and metformin hydrochloride extended-release tablets should take the two tablets together once daily.
- Individualize the dosage of sitagliptin and metformin hydrochloride extended-release tablets on the basis of the patient's current regimen, effectiveness, and tolerability.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin hydrochloride (HCl) extended-release.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release once 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 100 mg sitagliptin and the previously prescribed dose of metformin.
- For patients taking metformin hydrochloride immediate-release 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of sitagliptin and metformin hydrochloride extended-release tablets are two 50 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets taken together once daily.
- Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin hydrochloride immediate-release or sitagliptin and metformin extended-release and sitagliptin and metformin hydrochloride extended-release tablets.
- Do not split, crush or chew sitagliptin and metformin hydrochloride extended-release tablets.
- Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) ()2.2 Recommendations for Use in Renal Impairment
- Assess renal function prior to initiation of sitagliptin and metformin hydrochloride extended-release tablets and periodically thereafter.
- Sitagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2[see Contraindications and Warnings and Precautions ].
- Initiation of sitagliptin and metformin hydrochloride extended-release tablets in patients with an eGFR between 30 and 45 mL/min/1.73 m2is not recommended.
- In patients taking sitagliptin and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy and limit dose of the sitagliptin component to 50 mg once daily.
- Do not use in patients with eGFR below 30 mL/min/1.73 m2.
- Sitagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2.
- Limit dose of sitagliptin to 50 mg once daily if eGFR falls below 45 mL/min/1.73 m2.
- Sitagliptin and metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ()2.3 Discontinuation for Iodinated Contrast Imaging Procedures
Discontinue sitagliptin and metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart sitagliptin and metformin hydrochloride extended-release tablets if renal function is stable
[see Warnings and Precautions ].
Tablets:
- Sitagliptin 100 mg and metformin hydrochloride 1,000 mg extended-release tablets are reddish brown to brown colored, oval shaped, film-coated tablets debossed with "1806" on one side and plain on the other side.
- Sitagliptin 50 mg and metformin hydrochloride 500 mg extended-release tablets are light orange to beige colored, oval shaped, film-coated tablets debossed with "1804" on one side and plain on the other side.
- Sitagliptin 50 mg and metformin hydrochloride 1,000 mg extended-release tablets are yellow to beige colored, oval shaped, film-coated tablets debossed with "1805" on one side and plain on the other side.
- Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. ()8.3 Females and Males of Reproductive Potential
Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.
- Geriatric Use: Assess renal function more frequently. ()
8.5 Geriatric UseSitagliptin and metformin hydrochloride extended-release tabletsIn general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy and the higher risk of lactic acidosis. Renal function should be assessed more frequently in elderly patients
[see Contraindications (4), Warnings and Precautions (5.1, 5.4) and; Clinical Pharmacology (12.3)].SitagliptinOf the total number of subjects (N=3,884) in clinical studies of sitagliptin, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness of sitagliptin have been observed between subjects 65 years and over and younger.
MetforminControlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients.
- Hepatic Impairment: Avoid use in patients with hepatic impairment. ()8.7 Hepatic Impairment
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Sitagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with hepatic impairment
[see Warnings and Precautions (5.1)].
Sitagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (.)]5.1 Lactic Acidosis
There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels were generally >5 mcg/mL Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of sitagliptin and metformin hydrochloride extended-release tablets. In sitagliptin and metformin hydrochloride extended-release tablet-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis, and if these symptoms occur instruct them to discontinue sitagliptin and metformin hydrochloride extended-release tablets and report these symptoms to their health care provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
Renal ImpairmentThe postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include
[see Dosage and Administration and Clinical Pharmacology ]:- Before initiating sitagliptin and metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR).
- Sitagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR below 30 mL/min/1.73 m2[see Contraindications ].
- Initiation of sitagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with an eGFR between 30 and less than 45 mL/min/1.73 m2
- In patients taking sitagliptin and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.
- Obtain an eGFR at least annually in all patients taking sitagliptin and metformin hydrochloride extended-release tablets. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
Drug InteractionsThe concomitant use of sitagliptin and metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation
[see Drug Interactions ].Therefore, consider more frequent monitoring of patients.Age 65 or GreaterThe risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients
[see Use in Specific Populations ].Radiological Studies with ContrastAdministration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop sitagliptin and metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart sitagliptin and metformin hydrochloride extended-release tablets if renal function is stable.
Surgery and Other ProceduresWithholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Sitagliptin and metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic StatesSeveral of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue sitagliptin and metformin hydrochloride extended-release tablets.
Excessive Alcohol IntakeAlcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving sitagliptin and metformin hydrochloride extended-release tablets.
Hepatic ImpairmentPatients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of sitagliptin and metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
- A history of a serious hypersensitivity reaction to sitagliptin, metformin, or any of the excipients in sitagliptin and metformin hydrochloride extended-release tablets. Serious hypersensitivity reactions including anaphylaxis or angioedema have been reported [see Warnings and Precautions () and Adverse Reactions (5.7 Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of sitagliptin and metformin hydrochloride extended-release tablets. 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 sitagliptin and metformin hydrochloride extended-release tablets, assess for other potential causes for the event, and institute alternative treatment for diabetes
[see Adverse Reactions ].Angioedema has also been reported with other DPP-4 inhibitors Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with sitagliptin and metformin hydrochloride extended-release tablets.
)].6.2 Postmarketing ExperienceAdditional adverse reactions have been identified during postapproval use of sitagliptin with metformin, sitagliptin, or metformin. 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.
Skin and subcutaneous tissue disorders:hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, bullous pemphigoid, and exfoliative skin conditions including Stevens-Johnson syndromeRespiratory, thoracic and mediastinal disorders:upper respiratory tract infectionHepatobiliary disorders:hepatic enzyme elevations; cholestatic, hepatocellular, and mixed hepatocellular liver injuryGastrointestinal disorders:acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis, constipation, vomiting, mouth ulceration, stomatitisRenal and urinary disorders: worsening renal function, including acute renal failure (sometimes requiring dialysis) and tubulointerstitial nephritisMusculoskeletal and connective tissue disorders:severe and disabling arthralgia, myalgia, pain in extremity, back pain, pruritus, rhabdomyolysisNervous system disorders:headache.