Lactic Acidosis: Metformin HCl: Lactic acidosis is a rare but serious, metabolic complication that can occur due to metformin accumulation during treatment with Janumet; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin HCl is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In >20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure (CHF) requiring pharmacologic management, in particular those with unstable or acute CHF who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by the use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients ≥80 years unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin, since alcohol potentiates the effects of metformin HCl on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see Precautions).
The onset of lactic acidosis often is subtle and accompanied only by nonspecific symptoms eg, malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. The patient and patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see Hypoxic States on the following texts). Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and if indicated, blood pH, lactate levels and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal but <5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms eg, poorly controlled diabetes or obesity, vigorous physical activity or technical problems in sample handling.
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin HCl is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery (see Contraindications).
Pancreatitis: There have been post-marketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking Janumet. After initiation of Janumet, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, Janumet should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Janumet.
Impaired Hepatic Function: Since impaired hepatic function has been associated with some cases of lactic acidosis, Janumet should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Assessment of Renal Function: Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Janumet. In the elderly, Janumet should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function.
Before initiation of therapy with Janumet and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and Janumet discontinued if evidence of renal impairment is present.
Vitamin B12 Levels: In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with vitamin B12 absorption from the B12-intrinsic factor complex, is however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Janumet and any apparent abnormalities should be appropriately investigated and managed (see Adverse Reactions).
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 2- to 3-year intervals may be useful.
Alcohol Intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Janumet.
Surgical Procedures: Use of Janumet should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes: A patient with type 2 diabetes previously well controlled on Janumet who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and if indicated, blood pH, lactate, pyruvate and metformin levels. If acidosis of either form occurs, Janumet must be stopped immediately and other appropriate corrective measures initiated.
Use with Medications Known to Cause Hypoglycemia: Sitagliptin: When sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin (see Adverse Reactions). Therefore, patients also receiving an insulin secretagogue (eg, sulfonylurea) or insulin may require a lower dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia (see Dosage & Administration).
Metformin HCl: 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 (eg, sulfonylureas and insulin) or ethanol. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking β-adrenergic-blocking drugs.
Concomitant Medications Affecting Renal Function or Metformin Disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin eg, cationic drugs that are eliminated by renal tubular secretion (see Interactions), should be used with caution.
Radiologic Studies with Intravascular Iodinated Contrast Materials: Intravascular contrast studies with iodinated materials (eg, IV urogram, IV cholangiography, angiography and computed tomography (CT) scans with intravascular contrast materials) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see Contraindications). Therefore, in patients in whom any such study is planned, Janumet should temporarily discontinued at the time of or prior to the procedure and withheld for 48 hrs subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal.
Hypoxic States: Cardiovascular collapse (shock) from whatever cause, acute CHF, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. When such events occur in patients on Janumet therapy, the drug should be promptly discontinued.
Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to stress eg, fever, trauma, infection or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Janumet and temporarily administer insulin. Janumet may be reinstituted after the acute episode is resolved.
Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, 1 of the components of Janumet. These reactions include anaphylaxis, angioedema and exfoliative skin conditions, including Stevens-Johnson syndrome. 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. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the 1st dose. If a hypersensitivity reaction is suspected, discontinue Janumet, assess for other potential causes for the event and institute alternative treatment for diabetes (see Adverse Reactions).
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Janumet or any other antidiabetic drug.
Patient Counseling Information: Instructions: Patients should be informed of the potential risks and benefits of Janumet and of alternative modes
of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood-glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress eg, fever, trauma, infection, or surgery, medication requirements may change and patients should be
advised to seek medical advice promptly.
The risks of lactic acidosis due to the metformin component, its symptoms and conditions that predispose to its development, as noted in Warnings, should be explained to patients. Patients should be advised to discontinue Janumet immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heart beat, sensation of feeling cold (especially in the extremities) or other nonspecific symptoms occur. Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of Janumet therapy; however, patients should consult their physician if they
develop unexplained symptoms. Although gastrointestinal symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious disease.
Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving Janumet.
Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with Janumet.
Patients should be informed that acute pancreatitis has been reported during post-marketing use of Janumet. Patients should be informed that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue Janumet and contact their physician if persistent severe abdominal pain occurs (see previously mentioned).
Patients should be informed that the incidence of hypoglycemia is increased when Janumet is added to an insulin secretagogue (eg, sulfonylurea) or insulin therapy and that a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
Patients should be informed that allergic reactions have been reported during post-marketing use of sitagliptin, 1 of the components of Janumet. If symptoms of allergic reactions (including rash, hives, and swelling of the face, lips, tongue and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking Janumet and seek medical advice promptly.
Physicians should instruct their patients to read the patient package insert before starting Janumet therapy and to reread each time the prescription is renewed. Patients should be instructed to inform the physician if any bothersome or unusual symptom develops or if any symptom persists or worsens.
Laboratory Tests: Response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C levels, with a goal of decreasing these levels towards the normal range. A1C is especially useful for evaluating long-term glycemic control.
Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, vitamin B12 deficiency should be excluded.
Use in pregnancy: Janumet: There are no adequate and well controlled studies in pregnant women with Janumet or its individual components; therefore, the safety of Janumet in pregnant women is not known. Janumet should be used during pregnancy only if clearly needed.
No animal studies have been conducted with the combined products in Janumet to evaluate effects on reproduction. The following data are based on findings in studies performed with sitagliptin or metformin individually.
Sitagliptin: Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are however, no adequate and well controlled studies with sitagliptin in pregnant women.
Sitagliptin administered to pregnant female rats and rabbits from gestation day 6-20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits) or approximately 30 and 20 times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg or approximately 100 times human exposure at the MRHD.
Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.
Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hrs and 80% at 24 hrs post-dose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hrs and 30% at 24 hrs.
Metformin HCl: Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Use in lactation: No studies in lactating animals have been conducted with the combined components of Janumet. In studies performed with the individual components, both sitagliptin and metformin are secreted in the milk of lactating rats. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Janumet is administered to a nursing woman.
Use in children: Safety and effectiveness of Janumet in pediatric patients <18 years have not been established.
Use in the elderly: Janumet: Because sitagliptin and metformin are substantially excreted by the kidney and because aging can be associated with reduced renal function, Janumet should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function (see Pharmacokinetics: Pharmacology under Actions).
Sitagliptin: Of the total number of subjects (N=3884) in phase II and III clinical studies of sitagliptin, 725 patients were ≥65 years, while 61 patients were ≥75 years. No overall differences in safety or effectiveness were observed between subjects ≥65 years 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 HCl: 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. Metformin should only be used in patients with normal renal function. The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function (see Pharmacology: Pharmacokinetics under Actions and Contraindications).