Janumet XR Special Precautions

Lactic Acidosis: Metformin hydrochloride: 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 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 JANUMET XR and report these symptoms to their healthcare 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 as follows: 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 Recommendations for Use in Renal Impairment under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions): 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).
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 Interactions: 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 (see 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 the Elderly as follows).
Radiological Studies with Contrast: Intravascular administration of iodinated contrast agents may lead to contrast-induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. JANUMET XR should be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see Dosage & Administration).
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. JANUMET XR 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 JANUMET XR.
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 JANUMET XR.
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 JANUMET XR in patients with clinical or laboratory evidence of hepatic disease.
Pancreatitis: 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 JANUMET XR, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUMET XR 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 XR.
Assessment of Renal Function: Metformin and sitagliptin are substantially excreted by the kidney.
Metformin hydrochloride: JANUMET XR is contraindicated in patients with severe renal impairment (see Contraindications and Lactic Acidosis as previously mentioned).
Sitagliptin: There have been postmarketing reports of worsening renal function in patients taking sitagliptin with or without metformin, including acute renal failure, sometimes requiring dialysis. An eGFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at an increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months. JANUMET XR should be 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 XR and any apparent abnormalities should be appropriately investigated and managed (see Clinical Trials Experience under Adverse Reactions).
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.
Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes: A patient with type 2 diabetes previously well controlled on JANUMET XR 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 XR 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). 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 Insulin Secretagogues or Insulin under Interactions).
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.
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 XR and temporarily administer insulin. JANUMET XR 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 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 Postmarketing Experience under Adverse Reactions).
Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUMET XR.
Bullous Pemphigoid: Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving JANUMET XR. If bullous pemphigoid is suspected, JANUMET XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET XR or any other anti-diabetic drug.
Renal Impairment: JANUMET XR: 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 (see Recommendations for Use in Renal Impairment under Dosage & Administration; Contraindications; Lactic Acidosis under Precautions; and Pharmacology: Pharmacokinetics under Actions).
Sitagliptin: Sitagliptin is excreted by the kidney, and sitagliptin exposure is increased in patients with renal impairment.
Metformin hydrochloride: Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment.
Hepatic 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 (see Lactic Acidosis under Precautions).
Use in Children: The safety and effectiveness of JANUMET XR have not been established in pediatric patients. Three 20-week double-blind, placebo-controlled studies each with 34-week extensions were conducted to evaluate the efficacy and safety of sitagliptin in 410 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes, with or without insulin therapy (HbA1c 6.5-10% for patients not on insulin, HbA1c 7-10% for patients on insulin). At study entry, patients in study 1 were not treated with oral antihyperglycemic agents; patients in studies 2 and 3 were on maximally tolerated metformin therapy. The primary efficacy endpoint was the change from baseline in HbA1c after 20 weeks of therapy. The pre-specified primary efficacy analyses included data from study 1 and pooled data from studies 2 and 3, regardless of glycemic rescue or treatment discontinuation.
In both efficacy analyses, the effect of treatment with sitagliptin was not significantly different from placebo. In study 1, the mean baseline HbA1c was 7.5%, and 12% of patients were on insulin therapy. At week 20, the change from baseline in HbA1c in patients treated with sitagliptin (N=95) was 0.06% compared to 0.23% in patients treated with placebo (N=95), a difference of -0.17% (95% CI: -0.62, 0.28). In studies 2 and 3, the mean baseline HbA1c was 8.0%, 15% of patients were on insulin and 72% were on metformin HCl doses of greater than 1,500 mg daily. At week 20, the change from baseline in HbA1c in patients treated with sitagliptin (N=107) was -0.23% compared to 0.09% in patients treated with placebo (N=113), a difference of -0.33% (95% CI: -0.70, 0.05).
Use in the Elderly: JANUMET XR: Because sitagliptin and metformin are substantially excreted by the kidney, and because aging can be associated with reduced renal function, renal function should be assessed more frequently in elderly patients (see Lactic Acidosis and Assessment of Renal Function as previously mentioned and Pharmacology: Pharmacokinetics under Actions).
Sitagliptin: Of the total number of subjects (N=3884) in premarketing Phase II and III 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.
Metformin hydrochloride: Controlled 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. In 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 of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients (see Contraindications, Assessment of Renal Function as previously mentioned and Pharmacology: Pharmacokinetics under Actions).