Dosage & Administration
By using PrescriberAI, you agree to the AI Terms of Use.
Janumet XR Prescribing Information
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 JANUMET XR. In JANUMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin 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 JANUMET XR 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
- Before initiating JANUMET XR, obtain an estimated glomerular filtration rate (eGFR).
- JANUMET XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Discontinue JANUMET XR if the patient's eGFR later falls below 30 mL/min/1.73 m2[see Contraindications (4)].
- Initiation of JANUMET XR is not recommended in patients with eGFR between 30 and 45 mL/min/1.73 m2.
- In patients taking JANUMET XR 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 JANUMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
The concomitant use of JANUMET XR 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
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
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 JANUMET XR 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 JANUMET XR if renal function is stable.
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. JANUMET XR should be temporarily discontinued while patients have restricted food and fluid intake.
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 JANUMET XR.
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 JANUMET XR.
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 JANUMET XR in patients with clinical or laboratory evidence of hepatic disease.
- Assess renal function prior to initiation of JANUMET XR and periodically thereafter.
- JANUMET XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. Discontinue JANUMET XR if the patient's eGFR later falls below 30 mL/min/1.73 m2[see Contraindications (4)and Warnings and Precautions (5.1)].
- Initiation of JANUMET XR in patients with an eGFR between 30 and 45 mL/min/1.73 m2is not recommended.
- In patients taking JANUMET XR 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.
JANUMET XR is contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/min/1.73 m2)[see Warnings and Precautions (5.1)].
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
- History of a serious hypersensitivity reaction to JANUMET XR, sitagliptin, or metformin such as anaphylaxis or angioedema.[See Warnings and Precautions (5.7); Adverse Reactions (6.2).]
- Severe renal impairment: eGFR below 30 mL/min/1.73 m2.
- Metabolic acidosis, including diabetic ketoacidosis.
- History of a serious hypersensitivity reaction (e.g., anaphylaxis or angioedema) to JANUMET XR, sitagliptin, or metformin.
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 JANUMET XR. In JANUMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin 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 JANUMET XR 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
- Before initiating JANUMET XR, obtain an estimated glomerular filtration rate (eGFR).
- JANUMET XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Discontinue JANUMET XR if the patient's eGFR later falls below 30 mL/min/1.73 m2[see Contraindications (4)].
- Initiation of JANUMET XR is not recommended in patients with eGFR between 30 and 45 mL/min/1.73 m2.
- In patients taking JANUMET XR 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 JANUMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
The concomitant use of JANUMET XR 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
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
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 JANUMET XR 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 JANUMET XR if renal function is stable.
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. JANUMET XR should be temporarily discontinued while patients have restricted food and fluid intake.
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 JANUMET XR.
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 JANUMET XR.
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 JANUMET XR in patients with clinical or laboratory evidence of hepatic disease.
Table 4presents clinically significant drug interactions with JANUMET XR:
| Carbonic Anhydrase Inhibitors | |
|---|---|
Clinical Impact: | Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with JANUMET XR may increase the risk for lactic acidosis. |
Intervention: | Consider more frequent monitoring of these patients. |
Examples: | Topiramate, zonisamide, acetazolamide or dichlorphenamide. |
Drugs that Reduce Metformin Clearance | |
Clinical Impact: | Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)]. |
Intervention: | Consider the benefits and risks of concomitant use with JANUMET XR. |
Examples: | Ranolazine, vandetanib, dolutegravir, and cimetidine. |
Alcohol | |
Clinical Impact: | Alcohol is known to potentiate the effect of metformin on lactate metabolism. |
Intervention: | Warn patients against alcohol intake while receiving JANUMET XR. |
Insulin Secretagogues or Insulin | |
Clinical Impact: | Coadministration of JANUMET XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. |
Intervention: | Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. |
Drugs Affecting Glycemic Control | |
Clinical Impact: | Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. |
Intervention: | When such drugs are administered to a patient receiving JANUMET XR, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving JANUMET XR, observe the patient closely for hypoglycemia. |
Examples: | Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. |
- Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring.
- Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use.
- Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake.
The dose of the sitagliptin component should be limited to 50 mg once daily if eGFR falls below 45 mL/min/1.73 m2. JANUMET XR is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m2.
Sitagliptin is excreted by the kidney, and sitagliptin exposure is increased in patients with renal impairment.
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment.
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. JANUMET XR is not recommended in patients with hepatic impairment.
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 JANUMET XR. In JANUMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin 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 JANUMET XR 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
- Before initiating JANUMET XR, obtain an estimated glomerular filtration rate (eGFR).
- JANUMET XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Discontinue JANUMET XR if the patient's eGFR later falls below 30 mL/min/1.73 m2[see Contraindications (4)].
- Initiation of JANUMET XR is not recommended in patients with eGFR between 30 and 45 mL/min/1.73 m2.
- In patients taking JANUMET XR 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 JANUMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
The concomitant use of JANUMET XR 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
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
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 JANUMET XR 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 JANUMET XR if renal function is stable.
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. JANUMET XR should be temporarily discontinued while patients have restricted food and fluid intake.
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 JANUMET XR.
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 JANUMET XR.
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 JANUMET XR in patients with clinical or laboratory evidence of hepatic disease.
JANUMET® XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- Take JANUMET XR orally once daily with a meal. Patients taking two JANUMET XR tablets should take the tablets together. ()
2.1 Recommended Dosing- Take JANUMET XR orally once daily with a meal. Patients taking two JANUMET XR tablets should take the two tablets together once daily.
- Individualize the dosage of JANUMET XR on the basis of the patient’s current regimen, effectiveness, and tolerability.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2000 mg of metformin hydrochloride (HCl) extended-release.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1000 mg metformin HCl 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 HCl immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin and 1000 mg metformin HCl extended-release tablets taken together once daily.
- Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET (sitagliptin and metformin HCl immediate-release) and JANUMET XR.
- Do not split, crush or chew JANUMET XR tablets.
- Individualize the dosage of JANUMET XR on the basis of the patient’s current regimen, effectiveness, and tolerability. ()
2.1 Recommended Dosing- Take JANUMET XR orally once daily with a meal. Patients taking two JANUMET XR tablets should take the two tablets together once daily.
- Individualize the dosage of JANUMET XR on the basis of the patient’s current regimen, effectiveness, and tolerability.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2000 mg of metformin hydrochloride (HCl) extended-release.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1000 mg metformin HCl 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 HCl immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin and 1000 mg metformin HCl extended-release tablets taken together once daily.
- Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET (sitagliptin and metformin HCl immediate-release) and JANUMET XR.
- Do not split, crush or chew JANUMET XR tablets.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2000 mg of metformin HCl extended-release. ()
2.1 Recommended Dosing- Take JANUMET XR orally once daily with a meal. Patients taking two JANUMET XR tablets should take the two tablets together once daily.
- Individualize the dosage of JANUMET XR on the basis of the patient’s current regimen, effectiveness, and tolerability.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2000 mg of metformin hydrochloride (HCl) extended-release.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1000 mg metformin HCl 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 HCl immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin and 1000 mg metformin HCl extended-release tablets taken together once daily.
- Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET (sitagliptin and metformin HCl immediate-release) and JANUMET XR.
- Do not split, crush or chew JANUMET XR tablets.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1000 mg metformin HCl once daily, with gradual dose escalation recommended to reduce the gastrointestinal effects due to metformin. ()
2.1 Recommended Dosing- Take JANUMET XR orally once daily with a meal. Patients taking two JANUMET XR tablets should take the two tablets together once daily.
- Individualize the dosage of JANUMET XR on the basis of the patient’s current regimen, effectiveness, and tolerability.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2000 mg of metformin hydrochloride (HCl) extended-release.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1000 mg metformin HCl 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 HCl immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin and 1000 mg metformin HCl extended-release tablets taken together once daily.
- Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET (sitagliptin and metformin HCl immediate-release) and JANUMET XR.
- Do not split, crush or chew JANUMET XR 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 HCl 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin and 1000 mg metformin HCl extended-release tablets once daily. ()
2.1 Recommended Dosing- Take JANUMET XR orally once daily with a meal. Patients taking two JANUMET XR tablets should take the two tablets together once daily.
- Individualize the dosage of JANUMET XR on the basis of the patient’s current regimen, effectiveness, and tolerability.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2000 mg of metformin hydrochloride (HCl) extended-release.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1000 mg metformin HCl 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 HCl immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin and 1000 mg metformin HCl extended-release tablets taken together once daily.
- Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET (sitagliptin and metformin HCl immediate-release) and JANUMET XR.
- Do not split, crush or chew JANUMET XR tablets.
- Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET and JANUMET XR. ()
2.1 Recommended Dosing- Take JANUMET XR orally once daily with a meal. Patients taking two JANUMET XR tablets should take the two tablets together once daily.
- Individualize the dosage of JANUMET XR on the basis of the patient’s current regimen, effectiveness, and tolerability.
- The maximum recommended daily dose is 100 mg of sitagliptin and 2000 mg of metformin hydrochloride (HCl) extended-release.
- The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1000 mg metformin HCl 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 HCl immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin and 1000 mg metformin HCl extended-release tablets taken together once daily.
- Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET (sitagliptin and metformin HCl immediate-release) and JANUMET XR.
- Do not split, crush or chew JANUMET XR 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 JANUMET XR and periodically thereafter.
- JANUMET XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. Discontinue JANUMET XR if the patient's eGFR later falls below 30 mL/min/1.73 m2[see Contraindications (4)and Warnings and Precautions (5.1)].
- Initiation of JANUMET XR in patients with an eGFR between 30 and 45 mL/min/1.73 m2is not recommended.
- In patients taking JANUMET XR 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.
- Discontinue if eGFR later falls below 30 mL/min/1.73 m2.
- Initiation is not recommended in patients with eGFR between 30 – 45 mL/min/1.73 m2.
- Assess risk/benefit of continuing if eGFR falls below 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.
- JANUMET XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ()
2.3 Discontinuation for Iodinated Contrast Imaging ProceduresDiscontinue JANUMET XR 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 JANUMET XR if renal function is stable
[see Warnings and Precautions (5.1)].
Tablets:
- sitagliptin 100 mg and metformin HCl 1000 mg extended-release tablets are blue, bi-convex oval, film-coated tablets with “81” debossed on one side.
- sitagliptin 50 mg and metformin HCl 500 mg extended-release tablets are light blue, bi-convex oval, film-coated tablets with “78” debossed on one side.
- sitagliptin 50 mg and metformin HCl 1000 mg extended-release tablets are light green, bi-convex oval, film-coated tablets with “80” debossed on one side.
- Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. ()
8.3 Females and Males of Reproductive PotentialDiscuss 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 UseJANUMET XRIn 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); Clinical Pharmacology (12.3).]SitagliptinOf the total number of subjects (N=3884) 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 were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
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 ImpairmentUse of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. JANUMET XR is not recommended in patients with hepatic impairment.
[See Warnings and Precautions (5.1).]
JANUMET XR is contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see.]
5.1 Lactic AcidosisThere 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 JANUMET XR. In JANUMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin 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 JANUMET XR 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 (2.2), Clinical Pharmacology (12.3)]:- Before initiating JANUMET XR, obtain an estimated glomerular filtration rate (eGFR).
- JANUMET XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Discontinue JANUMET XR if the patient's eGFR later falls below 30 mL/min/1.73 m2[see Contraindications (4)].
- Initiation of JANUMET XR is not recommended in patients with eGFR between 30 and 45 mL/min/1.73 m2.
- In patients taking JANUMET XR 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 JANUMET XR. 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 JANUMET XR 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 (7)].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 (8.5)].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 JANUMET XR 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 JANUMET XR 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. JANUMET XR 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 JANUMET XR.
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 JANUMET XR.
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 JANUMET XR in patients with clinical or laboratory evidence of hepatic disease.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
- History of a serious hypersensitivity reaction to JANUMET XR, sitagliptin, or metformin such as anaphylaxis or angioedema. [See;
5.7 Hypersensitivity ReactionsThere have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET XR. 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 XR, assess for other potential causes for the event, and institute alternative treatment for diabetes.
[See Adverse Reactions (6.2).]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 JANUMET XR.
.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.
Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome
;upper respiratory tract infection; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis[see Indications and Usage (1)];worsening renal function, including acute renal failure (sometimes requiring dialysis) and tubulointerstitial nephritis; severe and disabling arthralgia; bullous pemphigoid; constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus; mouth ulceration; stomatitis; cholestatic, hepatocellular, and mixed hepatocellular liver injury; rhabdomyolysis.]